Komala Pillay

Predictive Value of Tumor Ki-67 Expression in Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studies.

Chemoendocrine Compared With Endocrine Adjuvant Therapies for Node-Negative Breast Cancer: Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors—International Breast Cancer Study Group

PURPOSE To centrally assess estrogen receptor (ER) and progesterone receptor (PgR) levels by immunohistochemistry and investigate their predictive value for benefit of chemo-endocrine compared with endocrine adjuvant therapy alone in two randomized clinical trials for node-negative breast cancer. PATIENTS AND METHODS International Breast Cancer Study Group Trial VIII compared cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for 6 cycles followed by endocrine therapy with goserelin with either modality alone in pre- and perimenopausal patients. Trial IX compared three cycles of CMF followed by tamoxifen for 5 years versus tamoxifen alone in postmenopausal patients. Central Pathology Office reviewed 883 (83%) of 1,063 patients on Trial VIII and 1,365 (82%) of 1,669 on Trial IX and determined ER and PgR by immunohistochemistry. Disease-free survival (DFS) was compared across the spectrum of expression of each receptor using the Subpopulation Treatment Effect Pattern Plot methodology. RESULTS Both receptors displayed a bimodal distribution, with substantial proportions showing no staining (receptor absent) and most of the remainder showing a high percentage of stained cells. Chemo-endocrine therapy yielded DFS superior to endocrine therapy alone for patients with receptor-absent tumors, and in some cases also for those with low levels of receptor expression. Among patients with ER-expressing tumors, additional prediction of benefit was suggested in absent or low PgR in Trial VIII but not in Trial IX. CONCLUSION Low levels of ER and PgR are predictive of the benefit of adding chemotherapy to endocrine therapy. Low PgR may add further prediction among pre- and perimenopausal but not postmenopausal patients whose tumors express ER.

Kaposi sarcoma in children with HIV: a clinical series from Red Cross Children's Hospital

AIM The study aimed to assess the clinical presentation, diagnosis, and treatment of Kaposi sarcoma in our HIV-positive paediatric population; analyse the increase in Kaposi sarcoma with the HIV epidemic; and look at unique surgical presentations and their implications for gastrointestinal surveillance. The incidence of Kaposi sarcoma, a herpesvirus 8-associated neoplasm of endothelial cells, has increased with the onset of the HIV epidemic. Surgical interest was prompted by a case of Kaposi sarcoma presenting with intussusception. METHODS All HIV-positive children with Kaposi sarcoma from 2003 to 2007 were included in the study. A retrospective analysis of clinical data was performed. MAIN RESULTS There were 9 children who ranged in age from 1 to 10 years (median, 7.1 years). Clinical presentations included oropalatal and laryngeal disease (5), pleural effusion (2), inguinoscrotal and skin disease (4), lymph node involvement (3), and gastrointestinal disease with haemorrhage (2), including one as a result of intussusception. Most patients presented with more than one clinical area involved. CD4 counts ranged from 14 to 2105. Two patients developed Kaposi sarcoma on antiretroviral treatment (ART); the remaining patients were started on antiretroviral treatment at presentation. Two patients died from overwhelming disseminated disease and one patient was lost to follow-up. Chemotherapy was required to achieve remission in the remaining 6. Before the HIV epidemic, this hospital treated one patient with Kaposi sarcoma every 4 years; the incidence has now increased to 2 patients per year. CONCLUSION Kaposi sarcoma is an increasingly important paediatric cancer in the era of the HIV epidemic. The clinical presentation in children is commonly oropalatal and inguinoscrotal disease. Gastrointestinal involvement was highlighted by a presentation with intussusception. The surgeons role in diagnosis and management includes clinical recognition, biopsy, and definitive treatment.

RyR1 Deficiency in Congenital Myopathies Disrupts Excitation-Contraction Coupling

In skeletal muscle, excitation–contraction (EC) coupling is the process whereby the voltage‐gated dihydropyridine receptor (DHPR) located on the transverse tubules activates calcium release from the sarcoplasmic reticulum by activating ryanodine receptor (RyR1) Ca2+ channels located on the terminal cisternae. This subcellular membrane specialization is necessary for proper intracellular signaling and any alterations in its architecture may lead to neuromuscular disorders. In this study, we present evidence that patients with recessive RYR1‐related congenital myopathies due to primary RyR1 deficiency also exhibit downregulation of the alfa 1 subunit of the DHPR and show disruption of the spatial organization of the EC coupling machinery. We created a cellular RyR1 knockdown model using immortalized human myoblasts transfected with RyR1 siRNA and confirm that knocking down RyR1 concomitantly downregulates not only the DHPR but also the expression of other proteins involved in EC coupling. Unexpectedly, this was paralleled by the upregulation of inositol‐1,4,5‐triphosphate receptors; functionally however, upregulation of the latter Ca2+ channels did not compensate for the lack of RyR1‐mediated Ca2+ release. These results indicate that in some patients, RyR1 deficiency concomitantly alters the expression pattern of several proteins involved in calcium homeostasis and that this may influence the manifestation of these diseases.

Polymyositis in African HIV-infected subjects.

Polymyositis in HIV-infected subjects, clinically and pathologically resemble polymyositis in non-HIV-infected subjects. We report 14 consecutive HIV-associated polymyositis cases and compare specific features with 25 polymyositis cases seen over the same 6.5 year period. The HIV-polymyositis cases were all female and compared to the polymyositis cases were younger (median age 33 years, interquartile range (IQR) 29; 37 vs. 46 years, IQR 38; 52, p=0.002), and with 4-fold lower serum creatine kinase (CK) values (median 1158 vs. 5153IU/l; p=0.019). A definite clinical improvement on prednisone therapy was documented in eight HIV-polymyositis cases and one improved with anti-retroviral therapy alone. The recognition of HIV-polymyositis which is treatable, but may present with serum CK elevations less than twofolds above normal, is clinically relevant in sub-Saharan Africa where electromyography and muscle biopsies are not readily available.

A novel ACTA1 mutation resulting in a severe congenital myopathy with nemaline bodies, intranuclear rods and type I fibre predominance

We describe a severe congenital myopathy patient of Xhosa native African origin with a novel de novo p.Gly152Ala skeletal muscle α-actin gene (ACTA1) mutation, who died at 6 months of age. The muscle pathology demonstrated abundant cytoplasmic and intranuclear rods, core-like areas and the unusual feature of larger type I than type II fibres. Our results further expand the phenotypes associated with ACTA1 mutations and provide support for the hypothesis that the structural abnormalities seen are a pathological continuum dependent on the precise mutation and biopsy location. Our results also demonstrate the likely world-wide distribution of de novo mutations in this gene.

Epigenetic changes as a common trigger of muscle weakness in congenital myopathies

Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorders.

A Study to investigate the role of p27 and Cyclin E immunoexpression as a prognostic factor in early breast carcinoma

BackgroundCyclin E and p27 expression is easy to assess in human tissues by standard immunohistochemical techniques. Immunohistochemistry is cost effective, relatively easy to perform and will play more of a role in the future management of cancer. The aim of this study was to investigate the role of p27 and cyclin E immunoexpression as a prognostic factor in early breast carcinoma.MethodsCyclin E and p27 immunohistochemistry was performed on sixty six cases of breast carcinoma submitted over a five year period to the Division of Anatomical Pathology, Groote Schuur hospital; Whittaker and Associates; and PathCare. All tumours included in this study were less than 5 cm in diameter (pT1 and pT2 stage) and all the patients had wide local excisions performed. Follow up information was obtained from patient folders in the Department of Radiation Oncology.ResultsThere was no significant association of cyclin E and p27 expression with distant metastasis free survival (MFS) for all invasive carcinomas in contrast to grade, lymph node spread and vascular invasion. However, there was a statistically significant direct association of cyclin E with distant metastases in all invasive carcinomas, in the subgroup of infiltrating duct carcinomas (IDC) and in the node negative group when cyclin E was stratified as negative and positive (low/high). In this study of early breast carcinoma, only 9/66 cases showed cyclin E expression. Of these, four patients had distant metastases, one patient had a local recurrence and four patients were alive at last follow-up. Furthermore, cyclin E expression was significantly associated with grade, lymph node spread, oestrogen receptor status and histological type. None of the lobular carcinomas showed cyclin E positivity and only one case of lobular carcinoma presented with distant metastases.59/66 cases were positive (low/high) for p27 while seven cases were negative, 22 cases showed low expression and 37 cases demonstrated high p27 expression.p27 was significantly associated with oestrogen receptor status only for all invasive carcinomas and in the IDC group. There was no statistical relationship between p27 and cyclin E, but 50 (76%) tumours with positive p27 expression were negative for cyclin E. There were similar results for the invasive ductal carcinoma subgroup.ConclusionThis study shows that p27 and cyclin E are not good independent prognostic markers for early breast carcinoma in contrast to grade, lymph node spread and vascular invasion for all invasive carcinomas. However, cyclin E provides some prognostic value as there is a direct statistical association with the development of distant metastases. Many previous studies have correlated overexpression of cyclin E with an aggressive course. The inverse relationship between p27 and cyclin E expression which has been reported in the literature has been highlighted, but this was not statistically significant. Most cases showed positive p27 expression and negative Cyclin E expression. This may be due to the early stage of the disease.

Microbiological yield from induced sputum compared to oropharyngeal swab in young children with cystic fibrosis

BACKGROUND Standard respiratory sampling in young children with cystic fibrosis (CF) is by oropharyngeal swab (OPS) as they cannot spontaneously expectorate. Sputum induction (IS) has been poorly investigated in this population. We aimed to compare the bacteriological yield of OPS vs. IS in young children with CF. METHODS Sequentially paired OPS followed by IS samples was collected in children <5years of age attending a CF clinic in Cape Town, South Africa. RESULTS IS was successfully paired with OPS in 98/113 (85%) attempts in 32 children (mean±SD 19±16months), with no serious adverse events. IS culture yield for any CF-associated bacteria from IS was 46% vs. 28% from OPS (p=0.01). The sensitivity, specificity, PPV and NPV of OPS compared to IS in isolating CF-associated bacteria were 56%, 96%, 93%, and 72% respectively. CONCLUSION Sputum induction is feasible, safe and superior to OPS for detecting CF-associated bacteria in young children with CF.

Facio-Auriculo-Vertebral Sequence in Association with DiGeorge Sequence, Rokitansky Sequence, and Dandy-Walker Malformation: Case Report

Extreme variability of expression is characteristic of the facio-auriculo-vertebral sequence. Sporadic and familial cases have been reported with obvious etiologic heterogeneity. Most reports in the literature are of clinical cases. The purpose of this paper is to present a fetal autopsy case report of the facio-auriculo-vertebral sequence in association with DiGeorge sequence, Rokitansky sequence, and Dandy-Walker malformation. A standard neonatal autopsy was performed on a macerated female fetus, gestational age 29 wk. External examination of the fetus revealed hypoplastic right face, low-set microtic right ear, and macrostomia. Internal examination showed hypoplastic thymus and lungs, a type I truncus arteriosus, and ventricular septal defect. Both kidneys showed evidence of pelvi-ureteric junction obstruction. The ovaries and fallopian tubes were present with an absent uterus and vagina (Rokitansky sequence). In addition, Dandy-Walker malformation was identified. Microscopically, a single hypoplastic parathyroid gland was noted and there was cystic renal dysplasia. We report the sixth case of the facio-auriculo-vertebral sequence in association with Rokitansky sequence and the first case of this sequence in association with Dandy-Walker malformation. In addition, features of DiGeorge sequence were present.