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.

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.

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.

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

EPR, ENDOR, and special TRIPLE measurements of P(*+) in wild type and modified reaction centers from Rb. sphaeroides.

The influence of the protein environment on the primary electron donor, P, a bacteriochlorophyll a dimer, of reaction centers from Rhodobacter sphaeroides, has been investigated using electron paramagnetic resonance and electron nuclear double resonance spectroscopy. These techniques were used to probe the effects on P that are due to alteration of three amino acid residues, His L168, Asn L170, and Asn M199. The introduction of Glu at L168, Asp at L170, or Asp at M199 changes the oxidation/reduction midpoint potential of P in a pH-dependent manner (Williams et al. (2001) Biochemistry 40, 15403-15407). For the double mutant His L168 to Glu and Asn at L170 to Asp, excitation results in electron transfer along the A-side branch of cofactors at pH 7.2, but at pH 9.5, a long-lived state involving B-side cofactors is produced (Haffa et al. (2004) J Phys Chem B 108, 4-7). Using electron paramagnetic resonance spectroscopy, the mutants with alterations of each of the three individual residues and a double mutant, with changes at L168 and L170, were found to have increased linewidths of 10.1-11.0 G compared to the linewidth of 9.6 G for wild type. The Special TRIPLE spectra were pH dependent, and at pH 8, the introduction of aspartate at L170 increased the spin density ratio, rho (L)/rho (M), to 6.1 while an aspartate at the symmetry related position, M199, decreased the ratio to 0.7 compared to the value of 2.1 for wild type. These results indicate that the energy of the two halves of P changes by about 100 meV due to the mutations and are consistent with the interpretation that electrostatic interactions involving these amino acid residues contribute to the switch in pathway of electron transfer.

Fibroblastic rheumatism.

We report the first known South African case of fibroblastic rheumatism, a rare dermatoarthropathy. Our patient presented with the typical clinical features of a sudden-onset, erosive polyarthritis with cutaneous nodules and sclerodactyly. Significant functional loss occurred within a period of 3 to 4 months. X-rays of the hands showed a single erosion, whereas magnetic resonance imaging showed further erosions as well as soft tissue and synovial enhancement. The unique histologic findings of fibroblastic proliferation, thickened collagen, and dermal fibrosis confirmed the diagnosis of fibroblastic rheumatism. Our patient was treated with a combination of methotrexate and oral prednisolone with subsequent resolution of her synovitis/arthritis and no further progression of her sclerodactyly and associated functional loss. The course of fibroblastic rheumatism is known to vary and although multiple therapeutic options have been tried, the question remains whether any of the therapies alters the natural course of the disease. However, considering the probable role of lymphocytes and fibrogenic cytokines, an increased awareness with early diagnosis and treatment in the initial inflammatory stage may prevent the development of incapacitating joint sequelae.

A new type of minocycline-induced cutaneous hyperpigmentation.

Pigmentary disorders are recognized adverse effects of the semi-synthetic tetracycline derivative antibiotic, minocycline. Three distinct types of minocycline-induced cutaneous pigmentation have been described. Type I, blue-black pigmentation confined to sites of scarring or inflammation on the face; Type II, blue-grey circumscribed pigmentation of normal skin of the lower legs and forearms; and Type III, diffuse muddy brown pigmentation of normal skin accentuated in sun-exposed areas. We report two patients with acne vulgaris with a fourth type of minocycline-induced cutaneous pigmentation. They presented with circumscribed blue-grey pigmentation within acne scars confined to the back. Histology showed pigment within dendritic cells, and extracellularly throughout the dermis. Histochemistry identified a calcium containing melanin-like substance. Iron was absent. Immunohistochemistry confirmed some pigment-containing cells to be macrophages. Electron microscopy demonstrated electron-dense granules, free and membrane-bound, within macrophages and fibroblast-like cells. Energy-dispersive X-ray analysis confirmed the presence of calcium. Iron was absent. This fourth type of cutaneous minocycline hyperpigmentation may be a variant of Type I, but based on clinical, pathological and microanalytical differences, appears to be a new entity. The pigment may be a drug metabolite-protein complex chelated with calcium, or an insoluble minocycline-melanin complex. We propose a classification of cutaneous minocycline pigmentation based on clinico-pathological criteria.

Diagnostic aspects of cervical lymphadenopathy in children in the developing world: a study of 1,877 surgical specimens.

Chronic cervical lymphadenopathy is a common clinical problem frequently requiring surgical biopsy. To evaluate the characteristics of surgically excised cervical lymph nodes (LN) in children in a developing country, we studied 1,332 children less than 15 years old (1,877 surgically removed cervical LNs) over a 23-year period (1976-1999). Indications for biopsy included failure to respond to antibiotic therapy, rapid increase in size, hard, matted LNs in the preauricular, supraclavicular, and posterior triangle of the neck, and difficulty in diagnosis. Clinical and pathological characteristics investigated included age, malignancy, and granulomatous disease such as tuberculosis (tbc). The mean age was 7 years (tbc 5.8/neoplastic disease 8.5 years). Twenty LNs (1.5%) were histologically normal. There were 637 (47.8%) with nonspecific reactive lymphoid hyperplasia and 484 with chronic granulomatous changes (36.3%). Tuberculous lymphadenitis was confirmed in 332 of these (25%). In 181 (54.5%) Mycobacterium tuberculosis was cultured and a further 149 had acid-fast bacilli. Other granulomatous diseases identified included sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfmann disease) (3), syphilis (4), yaws (2), and toxoplasmosis (1). No mycobacteria other than M. tuberculosis were encountered. More than two-thirds (108) of 154 patients with neoplastic LN involvement had a lymphoma; in a further 10 lymphadenopathy was associated with leukemia. Pyogenic organisms were identified in 32, and 5 were positive for human immunodeficiency virus, 1 of whom had Kaposi's sarcoma. A second pathology was identified in 18 of the 637 cases of reactive lymphoid hyperplasia (3 with tuberculosis); in 15 (1.3%) a diagnosis of lymphoma was made from other sites (pleural fluid, etc.) within 6 months of initial biopsy. This represents a diagnostically difficult subgroup requiring further investigation. Chronic lymphadenopathy in children in developing countries has a high incidence of infective causes, including a significant incidence of M. tuberculosis. The incidence of serious pathology in more than one-half of the cervical LNs examined justifies aggressive surgical investigation.

Non-familial visceral myopathy: clinical and pathologic features of degenerative leiomyopathy.

Degenerative leiomyopathy (DL) is a distinctive form of acquired degenerative visceral myopathy of uncertain etiology that occurs largely in Africa and results in intestinal pseudo-obstruction (IP). In this review of 39 patients from the Western Cape region of South Africa, the mean age at presentation was 9.5 years (range 6 months to 16 years). Characteristic clinical features included a chronic, insidious history of repeated attacks of abdominal distension, abdominal pain, and vomiting. Marked gaseous distension with atony and IP, especially of the colon, was noted on X-ray films. Megacolon was the most common radiologic feature, but pseudo-obstruction extended proximally into the small intestine in some patients with advanced disease. In the majority of cases the condition was progressive and eventually affected the entire gastrointestinal (GI) tract.

Unusual variations of gastrointestinal smooth muscle abnormalities associated with chronic intestinal pseudo-obstruction.

The clinicopathological spectrum of gastrointestinal (GI) smooth-muscle abnormalities associated with chronic intestinal pseudo-obstruction (CIPO) includes numerous heterogeneous conditions that are often ill-defined and poorly understood. Primary GI smooth-muscle abnormalities include familial and sporadic forms. Secondary involvement of GI smooth-muscle may result from associated GI and systemic conditions, but is less frequent than in adults. This study documents the clinicopathological findings observed in 12 South African patients with unusual forms of visceral smooth-muscle abnormalities not conforming to the diagnostic criteria of known primary visceral myopathies at the Tygerberg and Red Cross Childrens' Hospitals over a 14-year period (July 1985 through January 1999). Congenital muscle defects occurred in 5 patients where layers of bowel-wall muscle were absent or attenuated. Idiopathic fibrosis and ultrastructural features of perinuclear and mitochondrial vacuolisation were noted in 2 patients. A 21-year-old female with long-standing pseudo-obstruction demonstrated diminished immunohistochemical expression of enteric alpha-smooth-muscle actin without associated muscular degeneration or fibrosis. A secondary complication of dermatomyositis (bowel perforation) occurred twice in 1 patient. In 3 further patients (1 each with anorectal malformation, long-segment Hirschsprung's disease, and intestinal neuronal dysplasia), muscle fibrosis appeared during progression of the pre-existing disease. Visceral myopathies are poorly understood conditions that may present with CIPO. Unusual variations occur that do not conform to the usual recognised histological patterns. Secondary involvement may also be more common than anticipated in children. The challenge to further understanding these uncommon conditions lies in timely diagnosis and identification of early, subtle signs. Optimal and extensive application of various diagnostic modalities, including the development of new diagnostic tools, is of considerable importance in identifying hitherto unexplained CIPO due to GI smooth-muscle abnormalities.

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.

Health-related quality of life and functional outcome measures for children with cerebral palsy.

The aim of this study was to examine measures of health-related quality of life (HRQL) in children with cerebral palsy (CP) by comparing scores of a generic HRQL measure, the Child Health Questionnaire (CHQ); a disease-specific HRQL measure for children with CP, the Caregiver Questionnaire (CQ); and a pediatric functional measure, the Wee-Functional Independence Measure (WeeFIM). Participants included 30 caregivers of children with CP. The caregivers' children were a mean age of 8 years 6 months (17 females, 13 males). The ethnic origin of the children was 18 African-American, 8 white, 3 Hispanic, and 1 Middle Eastern. Significant correlations were found between the CQ and WeeFIM total and subscale scores (r=0.388 to 0.641). There was no correlation between the CHQ and CQ total summary scores, but significant correlations were found between the CHQ subscales related to parent time and family cohesion and the CQ total and subscale scores (r=0.386 to 0.481). The lack of correlation between the CHQ and WeeFIM indicates HRQL and function are different constructs that cannot be inferred from each other. The fair relationship found between the CQ and WeeFIM suggests that the constructs measured in these two assessments overlap. The lack of correlation between the total summary scores of the CHQ and CQ suggests the CQ may be a more specific measure of HRQL for this population that reflects the impact of the child's condition on the caregiver.

Clinicopathological features of Meckel's diverticula in 32 patients, with emphasis on the presence of Helicobacter pylori.

Meckel's diverticula (MD) with areas of gastric heterotopia (metaplasia) are more likely to become symptomatic than those that contain mucosa of purely an intestinal type. Helicobacter pylori has been associated with the pathogenesis of various diseases. The aim of the study was to evaluate whether H. pylori could be identified within metaplastic gastric mucosa in MD. A retrospective evaluation of the histopathological features and the clinical presentation of patients with MD was undertaken. The study group included 32 cases (20 paediatric and 12 adults). The commonest modes of presentation were acute pain (25%), obstruction (19%), bleeding (12.5%) and hernias (9%). On histological examination, heterotopic gastric mucosa was noted to be present in 12 cases. Of these, 3 specimens were noted to have H. pylori organisms present using a specific immunostaining technique. Two patients had concurrent gastric biopsies; one stained positively for H. pylori but the second (1 mm biopsy) was rapid urease-test positive only. In conclusion, the study provides strong evidence that H. pylori may colonise heterotopic gastric mucosa in a minority of MD. H. pylori is apparently not involved in the pathogenesis of most cases of complicated MD. Nonetheless, all 3 patients who had evidence of H. pylori were symptomatic.

Nodular tuberculid: a report of four patients.

The tuberculids are hypersensitivity reactions to Mycobacterium tuberculosis (MTB) and include papulonecrotic tuberculid (PNT), lichen scrofulosorum, erythema induratum of Bazin (EIB), and phlebitic tuberculid. Papulonecrotic tuberculid displays papulonecrotic lesions mostly on the extensor surfaces of the limbs. Histopathology shows necrosis, granulomatous inflammation (GI), and occasionally vasculitis, usually in the superficial dermis. Erythema induratum of Bazin shows nodulo-ulcerative lesions on the posterior aspect of the legs. Histopathology reveals a septolobular panniculitis, necrosis, GI, and vasculitis. The Mantoux test is strongly positive and associated tuberculosis (TB) may be present in both conditions. MTB cannot be demonstrated with a Ziehl-Neelsen (ZN) stain or cultured. The polymerase chain reaction has demonstrated MTB DNA in PNT (50%) and EIB (25%). The tuberculids respond to full anti-TB treatment. We document four patients with nodules on the legs in whom the pathologic changes were situated in the deep dermis and adjacent subcutaneous fat. Nodular tuberculid (NT) is regarded as a suitable term for these lesions. All patients were female. Their ages were 19 months, 12 years, 17 years, and 5 years. All patients presented with nodules on the limbs. These nodules were approximately 1 cm in diameter, dull red or bluish-red, and nontender. Ulceration was not present. The number of nodules varied from a few to many. The Mantoux test was strongly positive in all the patients. Associated pulmonary TB was present in two patients. Histopathology showed GI (n = 4), vasculitis (n = 2), and coagulative necrosis (n = 2). A ZN stain was negative in each case. All patients received anti-TB treatment for 6 months [rifampicin (n = 4), isoniazid (n = 4), pyrazinamide (n = 4), and ethambutol (n = 2)]. At 12 months follow-up, skin and pulmonary lesions had resolved in all. Nodular tuberculid should be distinguished from arthropod bites and papular urticaria, dermal erythema multiforme, evolving vasculitis, evolving folliculitis, and erythema nodosum. Histopathologically NT should be distinguished from other causes of granulomatous vasculitis and GI with or without necrosis. In children with nodules on the limbs unresponsive to routine treatment, skin biopsy should be done to exclude NT. Nodular tuberculid represents a hybrid between PNT and EIB with characteristic clinicopathologic features and should be included in the classification of cutaneous TB.

Elevated tissue immunoglobulins in Hirschsprung's disease--indication of early immunologic response.

Hirschsprung's disease is of multifactorial origin including genetic as well as other region-specific neuroenvironmental factors as well as focal contact with the extracellular matrix. Immunological activity is elevated in patients with enterocolitis associated with Hirschsprung's disease suggesting an immunological role in HD. Increased expression of major histocompatibility complexes (MHC) class II antigens and ICAM-1 in the aganglionic segments of bowel further strengthen this association and suggest early immunologic involvement. In this study, immunoglobulin activity was biochemically assessed in surgically resected specimens of 23 patients with Hirschsprung's disease in whom there was no clinical or histological evidence of enterocolitis. IgG and IgM were significantly increased in segments of bowel histologically identified as aganglionic or transitional zone, suggesting an area of maximal immunological activity in the transitional zone. The lack of an increase in IgA immunoglobulin activity in the same bowel segments suggests that IgA response may be related to associated enterocolitis in HD. Elevated tissue IgG and IgM levels were observed in 5 neonates presenting within the first week of life and older patients did not have significantly higher immunoglobulin levels, suggesting that the immunological response was not part of an ongoing infection or progressive condition. Increased IgM in the neonatal period suggests an early immune response in Hirschsprung's disease and strengthens the hypothesis that the immune system may be involved in its pathogenesis. Possible causes include the effects of an antenatal infection or local microenvironmental influences on the differentiation or maturation of migrating neuroblasts of the enteric nervous system.