A model system for studying metastasis using the embryonic chick.

An assay capable of recovering individual viable rodent cells localized in various organs of the chick embryo is described. This assay is based on the differential sensitivity of chick and rodent cells to the cytotoxic drug ouabain. Utilizing this assay, the potential of the chick embryo as a model system for studying metastasis was examined. Several cell lines were characterized in three ways: (a) ability to form local tumors after cell application onto the chorioallantoic membrane; (b) ability to form macro- or microscopic metastasis in the embryo from chorioallantoic membrane tumors; (c) experimental metastatic ability following i.v. injection into chorioallantoic membrane veins. These results were compared with the results obtained from the ouabain-plating assay. We conclude that this assay permits detection of viable metastatic cells even when tumors cannot be detected and helps to overcome the time constraints that have, in the past, limited the usefulness of the chick embryo in modeling metastasis.

Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients.

There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families.

Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.

Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study.

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

Faulty sternotomy and complications after median sternotomy.

In 11 of 55 patients with complications of median sternotomy, a paramedian sternotomy has been detected by computed tomography or at reparative operation. The thin side of the sternum is easily broken by the closing wires, this being the cause of instability and probably dehiscence and consequent infection and osteomyelitis. Most of the 11 patients in this group had some other predisposing risk factors, such as obesity, prolonged aortic cross-clamp time, and prolonged respiratory assistance. We suggest that, if a paramedian sternotomy is diagnosed at the primary operation, special closure techniques should be undertaken. Each patient with early dehiscence of a median sternotomy should undergo a computed tomographic examination. If a paramedian sternotomy is proved, simple reclosure is inadvisable. Sternectomy and closure with muscle flaps are then indicated.

The danger in skin grafting the bare mediastinum after sternectomy for postcoronary bypass dehiscence.

We describe a patient who underwent coronary bypass grafting, after which severe mediastinitis and sternal osteomyelitis occurred. Repair after sternectomy was undertaken with a rectus-abdominis myocutaneous flap. The distal fifth of the flap underwent necrosis and was replaced by a meshed split-thickness skin graft. A year later, a clip marking one of the bypass grafts nearly eroded through the skin graft, endangering the bypass graft. The skin graft was removed by abrasion, and the bypass graft was covered with a pectoralis muscle flap. We recommend that skin grafting of a granulating wound over coronary artery bypass grafts be avoided if possible.

Postoperative catheterization and prophylactic antimicrobials in children with hypospadias.

A prospective study of 78 children who underwent 84 operations for correction of hypospadias was done. Of these, 54 had a transperineal indwelling Foley catheter for ten days after surgery and 30, a transurethral catheter. Forty-five randomly selected children received prophylactic antimicrobial therapy (sulfamethoxazole), and the remaining 39 children served as controls. Incidence of urinary tract infection was significantly higher in the control group (10 of 39) as compared with the treated group (3 of 45) in spite of the higher incidence of vesicoureteral reflux in the treated group. This suggests that prophylactic antimicrobial treatment may prevent urinary tract infection from prolonged indwelling catheterization.

Vesicoureteral reflux in boys with hypospadias.

Hypospadias in a congenital anomaly which in most cases has to be corrected surgically. We include micturition cystourethrography (MCU) in the preoperative workup of all these children as well as three months postoperatively. Meatal stenosis and müllerian duct remnants are known to occur in this condition, but vesicoureteral reflux (VUR) was an unexpected finding in many boys who were asymptomatic and had no evidence of urinary tract infection. Fifty-eight of 305 hypospadiacs, examined by MCU, proved to have reflux, most of them grade II. In 37, VUR was found before surgery and in the remaining 21 after surgical correction, many of them with meatal stenosis. In 10 patients reflux appeared in the postoperative period where there had been none in the preoperative study; 8 of the 10 had a postoperative stricture of the distal urethra, and VUR subsided in 4 after adequate dilatation. We conclude that vesicoureteral reflux is not uncommonly found in patients with hypospadias, even in those who are completely asymptomatic. We believe this is an additional incentive to include an MCU in the pre- and postoperative evaluation of patients with this anomaly.

Use of sunscreen is linked with elevated naevi counts in Israeli school children and adolescents.

Epidemiological evidence indicates that a fair complexion and exposure to solar radiation in early years contribute to the proliferation of naevi and subsequent melanoma risk. To determine whether protection from sunlight is associated with lower naevi counts, we examined the prevalence and risk factors of naevi in a sample of Israeli school pupils. Whole body counts of naevi were recorded in 974 out of 1312 (74.2%) recruited pupils (7 and 12 year olds) from Ramat-Gan and Jerusalem. Host characteristics and habits of sun exposure were obtained using questionnaires. In each age group and geographic area, the mean whole body naevi counts, adjusted for confounders, were higher among males, pupils of European-American descent, and those susceptible to sunburn. The contributions to naevi risk of fair skin colour and frequent recreational sun exposure were higher among 7 year olds. Regular sunscreen use contributed to the naevi risk for both age strata in Ramat-Gan (at age 7, rate ratio [RR] = 1.7, 95% confidence interval [CI] = 1.3-2.2; at age 12, RR = 1.5, 95% CI = 1.1-2.1). Among the younger age group in Ramat-Gan, even seldom compared with no use of sunscreen was associated with higher naevi counts (RR= 1.5, 95% CI = 1.2-2.0). Similar patterns were noted with the pupils from Jerusalem. In conclusion, the elevated naevi count with increased sunscreen use indicates that sunscreens apparently do not modify the genetic predisposition to naevi proliferation. For better protection of children and adolescents, including those who use sunscreens, from the naevogenic effect of solar radiation, they should be encouraged to limit their exposure and wear protective clothing when in the sun.

Infections and melanoma risk: results of a multicentre EORTC case-control study. European Organization for Research and Treatment of Cancer.

Immune function plays a prominent role in the defence against cutaneous malignant melanoma and the increased risk of melanoma development during immunosuppression. Since the immune system is challenged beyond its routine activity by an infection, the effect of previous infectious diseases on the risk of melanoma may also be crucial. In a European Organization for Research and Treatment of Cancer (EORTC) case-control study performed in six European countries and Israel, we compared the history of severe infections in 603 melanoma patients with that in 627 population controls. We calculated adjusted odds ratios (ORs) to estimate the effect of infectious diseases on melanoma risk. The ORs for melanoma risk were below 1 for nearly all types of infections (except two) if body temperature was not taken into consideration, and for all infections with a body temperature above 38.5 degrees C. In the latter category significantly lowered ORs were found for pulmonary tuberculosis (0.16; 95% confidence interval [CI] 0.01-0.98), Staphylococcus aureus infections (0.54; 95% CI 0.31-0.94), sepsis (0.23; 95% CI 0.06-0.70), influenza and related infections (0.65; 95% CI 0.48-0.86) and pneumonia (0.45; 95% CI 0.27-0.73). Analysis of the cumulative influence revealed a consistent pattern of results pointing to a reduction in melanoma risk with increasing numbers of recorded infections and fever height. This apparent dose-response relationship suggests a causal association. Speculations on the underlying mechanism include a Shwartzman-like phenomenon when melanoma formation precedes the infection and/or an infection-related Th1-cell activation preventing the establishment of the tumour.

Malignant melanoma of the head and neck. Clinical and immunological considerations.

Prolonged exposure to sun for long periods during most of the year has led to an increase in the frequency of malignant melanoma in Israel, especially for head and neck (H&N) melanoma. H & N melanoma is found in males more than in females and diagnosed when already locally advanced. The disease-free interval between treatment of the primary lesion and recurrence of the disease correlated with the patient's age and the depth of invasion according to Breslow. A higher recurrence rate correlated with male gender, location in the scalp, and the stage of the disease. Metastatic disease involved the lungs, liver, and brain and responded poorly to systemic therapy. Improved survival was related to female gender, early stage of the disease, low Breslow thickness, and location of the primary lesion elsewhere than the scalp. Immunologically, we found that the titers of antimelanoma antibodies in patients with metastatic disease originating in the area of the head and neck were higher than the titer in disease-free H & N melanoma patients (p = 0.05). Moreover, patients with metastatic H & N melanoma had a higher titer of antityrosinase antibodies compared with healthy subjects. These two types of antibodies might be used as markers for disease progression in H & N melanoma. The more aggressive character of H & N melanoma was not reflected by different titers of antimelanoma antibodies nor by antityrosinase antibodies in patients with H & N versus non-H & N melanoma.

Hair-bearing neck flap for upper-lip reconstruction in the male.

Reconstruction of the upper lip resulting in a hair-bearing area and a non-hair-bearing lining is described in two cases of full-thickness lip defects. A unipedicled neck flap was used in one case and a bipedicled neck flap in the other, both comprised of hair-bearing and adjacent non-hair-bearing areas. The neck flap has the advantages of providing the two layers of the lip, and the reconstructed lip is not too thick and is mobile and pliable, and the hair resembles lip hair in color, density, and quality. The multiple operative procedures can be performed under local anesthetic.

Hypospadias repair with subcutaneous suture and tissue adhesive for surface closure.

A combination of a running P.G.A. subcutaneous suture, reinforced by butyl-cyanoacrylate tissue adhesive for surface bonding of the skin, has enabled us to reduce our rate of fistula formation by about 50 percent in hypospdias repairs by the Denis Browne two-stage or the Horton-Devine one-stage procedure.

Blindness as a complication of subcutaneous nasal steroid injection.

Blindness as a result of steroid injection into areas adjacent to the eyes, namely the interior of the nose and eyelids, has been described in the otolaryngologic and ophthalmologic literature but at no time in the plastic surgery literature. We describe a case of permanent visual loss at the time of injection of a long-acting steroid to the dorsum of the nose for postrhinoplasty scarring. We suggest that before steroid injection for elective procedures, the patient be informed of all possible consequences of complications even if their occurrence is very rare.

The value of angiography prior to use of the latissimus dorsi myocutaneous flap.

In 5 patients studied, preoperative angiography showed the thoracodorsal artery to be patent in two--both of them then had successful transfers of latissimus dorsi myocutaneous flaps. Obliteration of this artery was apparent in 3 patients, precluding the operation. We suggest that selective preoperative angiography be performed in all patients in whom a latissimus dorsi myocutaneous flap transfer is being considered, as a patent thoracodorsal artery is essential to the success of this procedure.

Congenital aplasia cutis: nonsurgical treatment with a synthetic skin substitute.

A case is presented of a newborn with a large abdominal wall defect of aplasia cutis conservatively treated with a new skin substitute (Omiderm). Omiderm is a thin, transparent membrane that is relatively inelastic when dry and capable of absorbing water. This provides an optimal environment for wound healing by preventing microbial invasion. It is simple to apply and easily removed, and it adheres without glue or staples. It is transparent, permitting direct vision of the defect. By enhancing the epithelialization process, shorter hospitalization is required. The large area of aplasia cutis healed completely under the Omiderm within 6 weeks.

The S nipple-areola reconstruction.

Nipple reconstruction is performed as a last stage in breast reconstruction following mastectomy. Various methods of nipple reconstruction have been described, most of them utilizing either free composite grafts or local flaps. The main problem encountered using either method is the gradual absorption and flattening of the nipple. The technique we used in reconstructing 22 nipples, in preference over the various methods accepted in breast reconstruction, achieves a long-standing, protruding nipple constructed from two large local flaps raised from an S-shape design. The technique is simple and permits freedom in choosing the height of the nipple, even in the presence of a mastectomy scar. The size of the nipple thereby constructed is in excess of what was expected. Shrinkage occurs during the first 2 months, and the resulting size is more than adequate. The areola is reconstructed by a full-thickness skin graft harvested from a nonhairy area of the upper inner thigh. The local flaps lack the necessary color, which is achieved by tattooing.

Cystourethrography as an aid in the evaluation of hypospadias and its complications.

We report the use of micturating cystourethrography to demonstrate complications of the urethra in hypospadias. We recommend MCU to evaluate hypospadias, both before and after the surgical repair.

Clinical-radiological evaluation of poststernotomy wound infection.

The presumption that computed tomography is the "gold standard" imaging method for diagnosing poststernotomy sternal wound infection was never validated. This study was designed to evaluate the accuracy and role of computed tomography in diagnosing the extent of infectious complications following sternotomy. A high postoperative infection recurrence rate in our earliest cases (30 percent, 1984 to 1988) motivated us to assess whether this modality enables the surgeon to choose the optimal surgical approach, which will make it possible to reduce morbidity and mortality rates. Two-hundred three patients with poststernotomy sternal wound infections were operated upon between 1984 and 1993. All pertinent clinical and radiological data of these patients were collected retrospectively and reinterpreted by an unbiased radiologist; the radiological data were correlated both to the intraoperative clinical findings and to histological interpretation of the surgical specimens. The study group available for statistical analysis included 160 patients. Predictive statistical analysis confirmed that computed tomography is a highly reliable imaging method for identifying the different pathologies as soft tissue, sternum mediastinal infections, in sternal wound infection with overall sensitivity of 93.5 percent and specificity of 81.7 percent. New radiographic findings were identified for the distinction of costochondral infection. This complication was, and still is, a major deceptive clinical problem in these patients and the major contributor to recurrences. We propose a sternal wound infection classification system that outlines the recommended approach for each clinical-radiological condition. Since computerized tomography was found to be a highly accurate modality, we strongly believe that the surgeon should take its pathological-radiographic findings into serious consideration, even if there are no "clear-cut" clinical signs for an existing or recurring infection.

Sternal wound infection: our experience with 200 cases.

More than 200 patients with sternal wound infections have been treated in the Plastic Surgery Department of our Medical Center over the years 1984-1993. Most of these were referrals from other hospitals. In recent years, the cases have become more severe, partially due to the fact that cardiac surgeons tend to operate older and sicker patients more readily than they previously did. 80% of these were post coronary bypass surgery, and the others heart and heart-lung transplants, repair of congenital heart anomalies, valve replacements etc. Several of the cases were cardiac surgery re-do's. Risk factors for developing this complication, such as diabetes, obesity, technical errors of sternal incision, prolonged intubation, the use of aortic balloon, etc. will be discussed. Many of our earlier patients had chronic fistulae following conservative therapy with old treatment modalities. In recent years, patients are usually referred at the acute stage. Most patients undergo removal of sternum and ribs. Previously, reconstruction included mainly transfer of the rectus ahdominis muscle, whereas lately the pectoralis muscles is utilized. Omentum was used in only one case. The importance of pre-operative imaging procedures has been thoroughly studied in our series. Especially important is the definition of the extent of the infection, and localization of foreign bodies causing chronic infections, such as suture material, epicardial electrodes etc. A change in infectants has also been noticed. In the first half of the study period, Pseudomonas aeruginosa comprised at least 40%.(ABSTRACT TRUNCATED AT 250 WORDS)