A Profile and Three-Year Follow-Up of Patients with Basal Cell Carcinoma in the Western Cape, South Africa.

Background: Basal cell carcinoma (BCC) is an important malignancy in sub-Saharan Africa. There is a paucity of data regarding BCC in South Africa. Aims: To describe the clinicopathological features of patients presenting with BCC in a cohort of South African patients. Methods: This retrospective descriptive study reviewed the medical records of 149 patients with BCC who attended the dermatology clinic at Tygerberg Academic Hospital from September 2015 to August 2016. Demographic and clinical data of those patients with histologically proven BCC were retrieved from clinical records. The data included the assessment for BCC recurrence after three years (September 2016-August 2019). Results: Of 390 patients, 155 (39.7%) had histologically confirmed BCCs. Complete medical records were available for 149 of these patients, and most were male (55.7%) and white (85.9%) with a median age of 70 years. Most patients had their BCC lesions for 12 months (43.1%) before diagnosis. BCCs were mostly located on the head and neck area (58.1%). In most patients (72.0%), a diagnostic punch biopsy confirmed BCC. Plastic surgeons subsequently excised the BCC lesions in 74.0% of these patients. The most common histological subtype was nodular BCC (74.0%). The National Comprehensive Cancer Network (NCCN) risk of recurrence was approximately evenly distributed between high- (54.1%) and low-risk groups (45.9%). The major high-risk feature was the location (36.6%). Histologically confirmed BCC recurrence occurred in 9 of the 149 patients (3.7%) over three years. Conclusions: BCC represents a high burden of disease in our setting. Compared to existing studies, the BCCs in this study are clinically and histologically similar to international reports.

Activation of the myogenic lineage by MEF2A, a factor that induces and cooperates with MyoD.

Muscle enhancer factor-2A (MEF2A), a member of the MADS family, induced myogenic development when ectopically expressed in clones of nonmuscle cells of human clones, a function previously limited to the muscle basic helix-loop-helix (bHLH) proteins. During myogenesis, MEF2A and bHLH proteins cooperatively activate skeletal muscle genes and physically interact through the MADS domain of MEF2A and the three myogenic amino acids of the muscle bHLH proteins. Thus, skeletal myogenesis is mediated by two distinct families of mutually inducible and interactive muscle transcription factors, either of which can initiate the developmental cascade.

Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells.

The terminal differentiation of mammalian muscle cells requires the tumor suppressor retinoblastoma protein (Rb). Unlike their wild-type counterparts, multinucleated myotubes from mouse cells deficient in Rb (Rb-/-) were induced by serum to re-enter the cell cycle. Development of the myogenic phenotype in Rb-/- cells correlated with increased expression of p107, which interacted with myogenic transcription factors. Serum-induced cell cycle reentry, on the other hand, correlated with decreased p107 expression. Thus, although p107 could substitute for Rb as a cofactor for differentiation, it could not maintain the terminally differentiated state in Rb-/- myotubes.

Clinical and pathological features of acral melanoma in a South African population: A retrospective study.

BACKGROUND: Acral melanoma (AM) is a rare subtype of cutaneous melanoma (CM) that disproportionately affects skin of colour and carries a poorer prognosis than other melanoma subtypes. The poor prognosis is attributed to late diagnosis and subsequent relatively high Breslow thickness, but also to an intrinsic biological aggressiveness. Scientific data on AM from the developing world are limited and a need exists to characterise the disease further in the South African (SA) population. OBJECTIVES: To describe the clinical and pathological features of AM in an SA population. METHODOLOGY: A retrospective chart review characterised the demographics, clinical features and histological data of 66 patients diagnosed with AM between January 2010 and June 2016 at Tygerberg Academic Hospital, Cape Town, SA. RESULTS: Sixty-six patients with AM were identified from 335 patients diagnosed with CM during the set time frame. The mean age (standard deviation (SD)) was 61.5 (12.5) years. Forty-two (63.6%) of the patients were female (male/female ratio 1:1.75). The majority of patients diagnosed with AM were black (48.5%), and the proportion of AM in black patients with CM was 80.0%. Fifty-six AMs (84.8%) were located on the foot and 10 (15.2%) on the hand. The median duration of the lesion before diagnosis was 10 months (range 2 - 84) and the mean (SD) tumour size was 3.8 (2.2) cm at diagnosis. The mean Breslow thickness of all AMs at diagnosis was 5.2 mm (median 4.2  mm, range 0 - 22). Stage of disease was known in 41 patients, 23 (56.1%) of whom had at least stage III disease at diagnosis. Mean Breslow thickness for foot and hand melanomas was 4.9 mm (range 0 - 22) and 6.9 mm (range 0 - 13.3), respectively (p=0.2552). The mean Breslow thickness in the black population was 6.3 mm compared with 4.2 mm and 4.3 mm, respectively, in the white and coloured populations (p=0.178). Patients from outside the Western Cape Province (WC) presented with a mean Breslow thickness of 6.6 mm (range 0 - 14.5) and patients from the WC with a mean Breslow thickness of 4.9 mm (range 0 - 22) (p=0.3602). CONCLUSIONS: AMs accounted for a significant proportion of all CMs diagnosed. Patients presented with an advanced stage of disease at diagnosis, and further studies are needed to further investigate the reasons for delayed diagnosis.

c-myc gene inactivation during induced maturation of HL-60 cells. Transcriptional repression and loss of a specific DNAse I hypersensitive site.

The c-myc proto-oncogene is amplified and expressed at high levels in HL-60 cells, a cell line derived from a patient with acute promyelocytic leukemia. Upon induction to terminal maturation, expression of c-myc is greatly reduced. We have studied the level of gene expression at which the change in c-myc expression is controlled and the changes in chromatin configuration that accompany the repression of myc expression. We report here that the repression of myc expression with induced maturation is controlled at the level of transcription, and that reduced expression is accompanied by the loss of a single DNAse I hypersensitive site 0.9 kilobase pair upstream from the gene.

Expression of multiple Na+,K+-adenosine triphosphatase isoform genes in human hematopoietic cells. Behavior of the novel A3 isoform during induced maturation of HL60 cells.

Multiple isoenzymes of the Na+,K+-ATPase (alpha, alpha+, and alpha 3) have been identified by molecular cloning (Shull, G. E., J. Greeb, and J. B. Lingrel. 1986. Biochemistry. 25:8125-8132; and Schneider, J. W., R. W. Mercer, and E. J. Benz, Jr. 1987. Clin. Res. 35:585A. [Abstr.]). At least one of these, the alpha 3 chain, represents a novel form for which protein products and enzymatic activities are just beginning to be defined in rodents. We have recently demonstrated that expression of alpha 3 is largely confined to neuromuscular tissues of fetal and adult rats (Schneider, J. W., R. W. Mercer, M. Gilmore-Hebert, M. F. Utset, C. Lai, A. Greene, and E. J. Benz, Jr. 1988. Proc. Natl. Acad. Sci. USA. 85:284-288). We now report that certain human leukemia cell lines including HL60, HEL, and Molt 4 express mRNA for both alpha and alpha 3 isoforms of Na+,K+-ATPase; mRNA was not detected in several other cell lines, including K562 and U937; no cell lines expressed alpha+ mRNA. In uninduced HL60 cells, alpha 3 mRNA comprised 20-30% of total Na+,K+-ATPase mRNA. Furthermore, in HL60 and HEL cells, both alpha and alpha 3 mRNA declined after induction of maturation by DMSO, retinoic acid, or hemin. However, the reduction in alpha 3 mRNA was far more dramatic. alpha 3 mRNA virtually disappeared, but alpha mRNA declined by only approximately 50%. In contrast, when maturation of HL60 cells along the monocyte/macrophage lineage was induced by exposure to phorbol esters, alpha 3 mRNA remained abundant. Moreover, mRNA for the beta subunit of the Na+,K+-ATPase increased dramatically. Our results demonstrate that the alpha 3 isoform, formerly thought to be confined to neuromuscular tissues, is expressed in restricted lineages of hematopoietic origin. These leukemia cell lines should provide a useful model for analyzing regulation of the alpha 3 isoform gene and characterization of alpha 3 isoform activities.

Rat-brain Na,K-ATPase beta-chain gene: primary structure, tissue-specific expression, and amplification in ouabain-resistant HeLa C+ cells.

We deduced the complete amino acid sequence of the rat brain Na,K-ATPase beta-subunit from cDNA. The rat brain beta-subunit exhibits a high degree of primary sequence and secondary structural homology with the human and Torpedo beta-subunit polypeptides. Analysis of rat tissue RNA reveals that the beta-subunit gene encodes four separate mRNA species which are expressed in a tissue-specific fashion. In ouabain-resistant HeLa C+ cells, beta-subunit DNA sequences are amplified (approximately 20-fold) and beta-subunit mRNAs are overproduced relative to levels in parental HeLa cells. These results suggest that the beta-subunit plays an important role in Na,K-ATPase structure-function and in the mechanism underlying cellular resistance to the cardiac glycosides.

Calcific uraemic arteriolopathy (calciphylaxis) in patients on renal replacement therapy.

BACKGROUND: Calcific uraemic arteriolopathy (calciphylaxis) is an unusual and potentially fatal condition characterised by small-vessel calcification and ischaemic skin necrosis. It mainly affects patients with end-stage renal disease (ESRD) on haemodialysis, but may rarely occur in the absence of ESRD in conditions such as primary hyperparathyroidism, malignancy, alcoholic liver disease and connective tissue disease. METHODS: We reviewed the records of all patients diagnosed with calciphylaxis while on renal replacement therapy at Tygerberg Hospital, Cape Town, South Africa, between 1990 and 2014, to describe its presentation, course and final outcome. RESULTS: Nineteen patients developed calciphylaxis over this period. Their median age was 34 years and 13 (68.4%) were female. Fifteen (78.9%) had received a kidney transplant. All patients had painful skin lesions that rapidly progressed to infarction. Small-vessel calcification was seen on skin biopsy in 13 patients. Twelve patients had hyperparathyroidism. Several of the transplanted patients had been treated for graft rejection in the year preceding the diagnosis. Treatment consisted of good wound care and efforts to normalise serum calcium and phosphate levels. Five patients received an urgent parathyroidectomy. The outcome was fatal in 17 patients, with sepsis being the main cause of death. CONCLUSIONS: In our patients, calciphylaxis carried a worse prognosis than previously reported internationally. It should always be considered in the differential diagnosis of painful skin lesions in the dialysis or transplant patient.

Cardiotoxicity in signal transduction therapeutics: erbB2 antibodies and the heart.

Cardiotoxicity is a common and potentially devastating side effect of antineoplastic drug therapy. This empiric observation is seen as paradoxical given that the cardiomyocyte is considered to be a terminally differentiated cell. Despite the fact that these cells do not divide after birth, adult cardiomyocytes may become "innocent bystander" targets of anticancer drugs designed to interfere with cell signaling pathways in rapidly proliferating cells. In breast cancer clinical trials, treatment with the erbB2 receptor antibody trastuzumab combined with anthracyclines has been associated with an increased risk for the development of cardiac pump failure. Trastuzumab/anthracycline cardiomyopathy may be the first clinically significant cardiotoxicity to emerge from signal transduction therapeutics. The erbB2 receptor tyrosine kinase is known to have a critical role in cardiac development. In addition, erbB2 is thought to participate in an important pathway for growth, repair, and survival of adult cardiomyocytes as part of a signaling network that involves neuregulins and the neuregulin receptor erbB4. However, erbB2 levels in the adult heart are low when compared with the levels found in erbB2-overexpressing breast cancer cells that are the intended targets of trastuzumab therapy. Thus, trastuzumab-associated cardiotoxicity must be explained by some alternative mechanism. After confirming that trastuzumab is capable of inducing tyrosine phosphorylation of the human cardiomyocyte erbB2 protein, a novel system for culturing human myocardium was developed in our laboratory. We used this system to study the effects of trastuzumab on human cardiomyocytes in vitro and observed trastuzumab-induced structural and functional changes in human cardiomyocytes that were at least partially reversible with the addition of recombinant neuregulins. The results obtained in these experiments support a direct action of trastuzumab on human cardiomyocytes. In addition, these data provide insight regarding potential molecular mechanisms. Most importantly, these data draw attention to the inherent risk of cardiotoxicity associated with a newly emerging class of antineoplastic drugs that interfere with signal transduction pathways.

Detection and subtyping of human herpesvirus-8 in renal transplant patients before and after remission of Kaposi's sarcoma.

BACKGROUND: Kaposi's sarcoma (KS) is a complication of renal transplantation. If the human herpesvirus-8 (HHV-8) causes KS, the virus should be present in all KS lesions and be drastically reduced or cleared from involved tissue on remission of the KS. METHODS: Fourteen renal transplant patients with cutaneous KS, including autopsy material from two cases, were investigated for the presence of HHV-8. A second skin biopsy was taken from 11 survivors, after remission of KS, from normal skin in the same anatomical region as the first biopsy. Remission was induced by reduction or cessation of immunosuppression. A peripheral blood sample was collected simultaneously with the repeat biopsy. A nested polymerase chain reaction assay was used to detect HHV-8 DNA in the biopsy tissue and peripheral blood mononuclear cells followed by direct sequencing of polymerase chain reaction product to detect any nucleotide changes. RESULTS: HHV-8 DNA was detected in all the cutaneous KS and all the visceral KS samples, as well as a number of KS-free organs including the thyroid, salivary gland, and myocardium that have not been described before. Mutations in the viral DNA could be demonstrated in all patients. The mutations found were related more to that seen in AIDS-KS cases than that found in African endemic KS cases. HHV-8 sequences could be detected in follow-up frozen skin biopsies of five patients but were negative in the equivalent formalin-fixed specimens. Viral DNA was also detected in 2 of 11 peripheral blood mononuclear cell samples collected at the time of the follow-up skin biopsies. CONCLUSION: Reduction or withdrawal of immunosuppression allows the immune system to recover sufficiently to reduce viral replication with subsequent viral persistence and low grade viral replication that coincides with clinical remission of the KS lesions. This provides further evidence for the important etiological role played by HHV-8 in the pathogenesis of posttransplant KS.

Thymidine phosphorylase expression in Kaposi sarcoma.

AIMS: To examine the immunohistochemical distribution of thymidine phosphorylase (TP) in all clinicopathological subtypes of Kaposi sarcoma. METHODS: Thirty two biopsy specimens of Kaposi sarcoma (29 patients) were studied. Six of these patients represented classic, six endemic, eight HIV associated, seven post-immunosuppression/transplant related, and two unclassified variants of Kaposi sarcoma. The average age was 49 years (range 22-83 years) and the male: female ratio 24:5. Four samples of angiosarcoma and one of spindle cell haemangio-endothelioma were stained in parallel. All specimens were fixed in formalin, embedded in paraffin wax and processed routinely. Immunohistochemistry was carried out using an antibody directed against CD31 (JC70) and the monoclonal antibody P-GF.44C against TP. RESULTS: All biopsy specimens showed immunoexpression for TP. The spindle cell component stained more strongly than newly formed endothelium lined vessels and normal, resident vessels at a distance from the lesions. CONCLUSIONS: The strong immunoexpression of TP suggests up-regulation of TP and a role for TP in angiogensis in Kaposi sarcoma. The mechanism for the up-regulation of TP remains unknown, but viral infections may trigger it. The differential staining of the various cell components of Kaposi sarcoma also suggest that TP either plays a role in the differentiation and maturation of Kaposi sarcoma or is a reflection of such changes.

Motor assessment of cocaine/polydrug exposed infants at age 4 months.

Fifty nondrug-exposed infants and 74 cocaine/polydrug-exposed infants were evaluated on the Movement Assessment of Infants (MAI). The test provides an assessment of risk for motor dysfunction at age 4 months. There was a significant difference in total risk scores between the two groups of infants with cocaine-exposed infants having higher total risk scores (p less than .0001). Categorical risk scores revealed significant differences between the infants in muscle tone, primitive reflexes, and volitional movement with cocaine-exposed infants scoring more poorly in each category (p less than .0001). The groups scored differently on 11 of the 49 MAI items in those categories. Placement of infants within previously established ranges of risk scores (0-7 = no risk; 8-13 questionable risk; greater than 13 = high risk) revealed a significant difference in distribution between the two groups (p less than .0001). Earlier studies of the effects of intrauterine drug exposure have not revealed significant differences in motor development. The MAI demonstrated differential assessments of risk for motor dysfunction between cocaine-exposed and nondrug-exposed infants.

Field testing of the movement assessment of infants.

The purpose of this study was to compare the test results of normal 4-month-old infants on the Movement Assessment of Infants with the published Movement Assessment of Infants a priori profile. We tested 50 healthy 4-month-old infants (24 white, 20 black, 6 other races) on 65 Movement Assessment of Infants items, encompassing the categories of muscle tone, primitive reflexes, automatic reactions, and volitional movements. The total-risk score was a sum of categorical risk scores. A between-group analysis of variance showed that the total-risk scores did not differ significantly by sex or race. Thirty percent of the infants we tested had total-risk scores greater than 7, which differed significantly from the 15% in the original Movement Assessment of Infants data. On 18 of the 65 Movement Assessment of Infants items, more than 15% of our study sample had risk scores that differed from Movement Assessment of Infants profile normative scores. The results of our study suggest that the current Movement Assessment of Infants profile may not accurately reflect the normal motor behavior of a 4-month-old infant. Suggestions for revising the Movement Assessment of Infants are made that could improve the reliability and validity of the test.

Teratomas in infancy and childhood at Tygerberg Hospital, South Africa, 1973 to 1992.

OBJECTIVES: To document the childhood teratomas at Tygerberg Hospital and compare the profile with other African series. DESIGN: Retrospective review of the clinicopathologic features of 43 cases of childhood teratomas. Tumors were classified according to the World Health Organization criteria for germ cell tumors. SETTING: Tygerberg Hospital, University of Stellenbosch, Cape Town, South Africa. RESULTS: There were 26 mature, 15 immature, and 2 malignant teratomas. The most common sites were the ovaries and the sacrococcygeal region. Testicular teratomas were absent. The female-to-male ratio for black patients was 5.5:1. There was a peak age incidence in the first 4 years of life, with sacrococcygeal teratomas predominating. A second, smaller peak between 12 and 15 years was seen owing to ovarian teratomas. Immature teratomas presented at an earlier age than mature teratomas. The majority of ovarian teratomas occurred in patients of mixed race, whereas the extragonadal teratomas were distributed more evenly among the race groups. In black patients and patients of mixed race mature teratomas predominated, whereas in white patients immature teratomas were most common. CONCLUSIONS: The increased occurrence of teratomas among female patients, the large number of ovarian teratomas, the absence of testicular teratomas, and the low incidence of malignant teratomas correspond to the observations of other African series. Certain differences are apparent among the three race groups, namely, a high ratio of female-to-male patients in the black group, a predominance of ovarian teratomas in the mixed-race and black groups, and a predominance of extragonadal and immature teratomas in the white group.

Idiopathic annular submitral aneurysm associated with Takayasu's aortitis. A report of two cases.

The pathologic findings in two patients with idiopathic annular submitral left ventricular aneurysms and coexistent Takayasu's aortitis are documented. The evidence of chronic persistent myocarditis in one patient and marked myocardial fibrosis in the other supports two theoretical possibilities: first, the aneurysms may have an inflammatory etiology and, second, a common inflammatory process may have accounted for both the myocardial and the aortic lesions.

Effects of prenatal exposure to opioids on focused attention in toddlers during free play.

The goals of this study were: (1) to determine if 24-month-old children exposed to opioids show decreased focused attention during free play compared with children of the same age who were not prenatally exposed; (2) to identify medical and social risk factors other than drug exposure that are related to focused attention; and (3) to determine if mothers' teaching ability had an effect on attention. Focused attention was rated during a 3-minute free play session for 30 toddlers who were methadone-exposed and for 44 comparison toddlers. The mother teaching the child to use a toy was also rated separately from the free play session. There was no difference in focused attention of 24 month olds during free play based only on prenatal exposure. Despite group differences in medical and social risk factors, only maternal IQ was significantly related to focused attention. Maternal instruction was strongly related to focused attention and mediated the effects of maternal IQ on attention.

Reinforcer effectiveness as a function of reinforcer rate and magnitude: a comparison of concurrent performances.

Pigeons' pecks on each of two concurrently available response keys were reinforced under a variable-interval schedule that sometimes allotted food-pellet deliveries to one key and sometimes to the other. The keys differed in the number of reinforcements assigned to each and in the number of pellets delivered during each reinforcement. When the total quantity of food associated with each key during a session was constant, the proportion of responses to a key depended on the particular combinations of reinforcer rate and reinforcer magnitude scheduled on each key. A given quantity of food generated more responding on a key when it was delivered frequently in small amounts than when it was delivered infrequently in large amounts.

Choice between two-component chained and tandem schedules.

Pigeons were trained on a two-key choice procedure in which a pair of equal and concurrently available variable-interval schedules (initial links) arranged entry into one or the other of two mutually exclusive schedules (terminal links) that ended in primary reinforcement. The terminal links were two-component chained or tandem schedules. Responses during the initial links were distributed equally on the two keys whenever the terminal links were associated with the same sets of interreinforcement intervals. Whether or not the terminal-link interreinforcement intervals were the same on the two keys, initial-link responding was affected by neither the presence nor relative durations of differentially signalled components within a terminal-link schedule. The simplest interpretation of these results is that initial-link responding is maintained directly by delayed primary reinforcement, rather than conditioned reinforcement afforded by the stimuli correlated with the terminal-link schedule components. This finding suggests that aspects of chained schedule performance usually attributed to conditioned reinforcement might best be reinterpreted in terms of delayed primary reinforcement and various discriminative functions served by the component-correlated stimuli.