Failure to progress: breast and prostate cancer cell lines in developing targeted therapies.

Developing anticancer drugs from preclinical to clinical takes approximately a decade in a cutting-edge biomedical lab and still 97% of most fail at clinical trials. Cell line usage is critical in expediting the advancement of anticancer therapies. Yet developing appropriate cell lines has been challenging and overcoming these obstacles whilst implementing a systematic approach of utilizing 3D models that recapitulate the tumour microenvironment is prudent. Using a robust and continuous supply of cell lines representing all ethnic groups from all locales is necessary to capture the evolving tumour landscape in culture. Next, the conversion of these models to systems on a chip that can by way of high throughput cytotoxic assays identify drug leads for clinical trials should fast-track drug development while markedly improving success rates. In this review, we describe the challenges that have hindered the progression of cell line models over seven decades and methods to overcome this. We outline the gaps in breast and prostate cancer cell line pathology and racial representation alongside their involvement in relevant drug development.

Paediatric dermatofibrosarcoma protuberan-a case report in an Afro-Caribbean boy.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma, which rarely metastasizes, but it is locally aggressive with a propensity to recur. It usually affects persons of African descent and is extremely rare in childhood with a favourable prognosis. We present a case of paediatric dermatofibrosarcoma protuberans to the midline of the lower back of a 9-year-old Afro-Caribbean boy who was biopsied with a 2-mm margin. After histological confirmation, a 4-cm margin was then performed. Surveillance for recurrence, though none has been seen thus far after 6-month follow-up, will be done for at least 5 years and possibly longer, given this is the first case of this nature ever seen in our institution and the Caribbean region.

Pleomorphic hyalinizing angiectatic tumour of the lower back - a rare case and review of the literature.

Pleomorphic hyalinizing angiectatic tumour (PHAT) is a very rare low-grade indeterminate neoplasm of connective and other soft tissue, which is not known to metastasize though local recurrence has been documented. It most commonly presents in the lower extremities, but other anatomical locations have been described. This is the second known case of PHAT from the Caribbean region and adds to the limited reported cases of the condition in the literature.

Notchplasty is associated with decreased risk of anterior cruciate ligament graft revision.

PURPOSE: Despite influencing knee biomechanics and outcomes, the use of notchplasty at time of anterior cruciate ligament reconstruction (ACLR) has not been evaluated with regards to risk of secondary injury and revision. This study evaluates this association. METHODS: 42 patients (21.7-years, IQR = 19.0-27.5) that underwent primary then revision ACLR at a single institution were contrasted with a case matched control group of patients with grafts that did not fail. Patients were propensity score matched in a 1:2 ratio by age, gender, and date of index procedure. Post-hoc statistical correction was made for post-index procedure sports participation level. RESULTS: Notchplasty was performed in 2 of 42 cases that went on to revision, and in 31 of 84 cases in the control group (p < 0.001). This was associated with reduced rates of revision ACLR (OR = 0.085, 95%CI = 0.019-0.378). A significant difference was seen in the post-ACLR activity level between groups (p = 0.028), with post-hoc testing highlighting those returning to competitive sport to be more likely to require subsequent revision (OR = 9.647, 95%CI = 1.947-47.795). Notchplasty remained significantly associated with (reduced) risk of revision surgery, despite the observed variation in post-ACLR activity (p = 0.001). CONCLUSION: Individuals whose graft failed following ACLR were significantly less likely to have had notchplasty performed as part of their surgery than a control group who did not suffer graft reinjury. We propose that this may be due to decreased tensioning of the graft as the knee enters dynamic valgus, which may be of great relevance to athletes undergoing ACLR to enable return to sport.

Clinicopathological Factors Affecting Breast Cancer Survival in Jamaican Women: A Retrospective Review.

OBJECTIVE: Breast cancer is the leading cause of cancer affecting women worldwide. The survival rate is primarily affected by the stage of the disease and several other demographic and clinicopathological factors. METHODS: This study is a retrospective cohort study of female patients of the University Hospital of the West Indies diagnosed with breast cancer between 2011 and 2016. The age, tumor size, SBR/Nottingham grade, tumor histologic subtype, tumor molecular subtype, and survival status of the cohort on November 1, 2019, were determined. The data were summarized. Survival across each variable was compared using univariate log-rank tests, Cox proportional hazard models, and crude and adjusted models. A second wave analysis was performed excluding patients whose survival status was presumed. RESULTS: A total of 503 patients were analyzed. The overall survival rate at 1, 3, and 5 years were 96.4%, 84.9%, and 79.0%, respectively, for the entire cohort. The molecular subtype was the most significant clinicopathological factor affecting overall survival. A younger age < 40 years, higher histologic grade, estrogen receptor-negative breast cancers, invasive ductal type breast cancers, and T1 lesions were associated with poorer survival outcomes at 5 years. The findings were reproduced after a second wave analysis excluding patients who were presumed alive was applied. CONCLUSIONS: Breast cancer overall survival in Jamaica is consistent with that of other developing countries in the literature. This study is an important contribution to the growing body of literature available and aids to the overall understanding of the behavior of breast cancer locally.

Acrometastasis of the Lower Limb Carries a Poorer Prognosis: A Retrospective Cohort Study.

BACKGROUND: Bony metastasis distal to the knee is rare and often reported alongside metastasis distal to the elbow. We sought to provide empirical evidence of the epidemiology, presentation, and prognosis of lower limb acrometastasis, alongside investigation of the distribution of metastases present while lower limb acrometastases form. METHODS: This retrospective cohort study identified 44 radiologically confirmed cases of lower limb acrometastasis from a single region. Case note review facilitated the extraction of data relating to the stated aims. Patients were grouped by extent of metastasis at primary diagnosis. Mann-Whitney U test compared metastatic burden, and Kaplan-Meier analysis compared survival. RESULTS: Prostate and breast carcinoma were the most commonly diagnosed primary tumors. Sixty-eight acrometastatic lesions were identified, of which 70% presented asymptomatically. Lower limb acrometastasis was associated with metastatic disease at a significantly greater number of sites than those presenting with metastasis proximal to the knee only (P = .007) and conveyed a significantly worse survival than metastasis proximal to the knee or nil metastasis (P < .001). Median survival from diagnosis of lower limb acrometastasis was 1.0 year. CONCLUSION: Lower limb acrometastasis is associated with a large metastatic burden and occurs in the terminal year of disease. Radiological identification of cases reveals a distinct cohort of acrometastatic lesions, more likely to present asymptomatically, and arises from alternate primary carcinomas than those in previous literature. LEVELS OF EVIDENCE: Level IV: Case series.

Expanding the prostate cancer cell line repertoire with ACRJ-PC28, an AR-negative neuroendocrine cell line derived from an African-Caribbean patient.

Prostate cell lines from diverse backgrounds are important to addressing disparities in prostate cancer (PCa) incidence and mortality rates among Black men. ACRJ-PC28 was developed from a transrectal needle biopsy and established via inactivation of the CDKN2A locus and simultaneous expression of human telomerase. Characterization assays included growth curve analysis, immunoblots, IHC, 3D cultures, immunofluorescence imaging, confocal microscopy, flow cytometry, WGS, and RNA-Seq. ACRJ-PC28 has been passaged more than 40 times in vitro over 10 months with a doubling time of 45 hours. STR profiling confirmed the novelty and human origin of the cell line. RNA-Seq confirmed the expression of prostate specific genes alpha-methylacyl-CoA racemase (AMACR) and NKX3.1 and Neuroendocrine specific markers synaptophysin (SYP) and enolase 2 (ENO2) and IHC confirmed the presence of AMACR. Immunoblots indicated the cell line is of basal-luminal type; expresses p53 and pRB and is AR negative. WGS confirmed the absence of exonic mutations and the presence of intronic variants that appear to not affect function of AR, p53, and pRB. RNA-Seq data revealed numerous TP53 and RB1 mRNA splice variants and the lack of AR mRNA expression. This is consistent with retention of p53 function in response to DNA damage and pRB function in response to contact inhibition. Soft agar anchorage-independent analysis indicated that the cells are transformed, confirmed by principal component analysis (PCA) where ACRJ-PC28 cells cluster alongside other PCa tumor tissues, yet was distinct. The novel methodology described should advance prostate cell line development, addressing the disparity in PCa among Black men.

The Utilization and Benefits of Telehealth Services by Health Care Professionals Managing Breast Cancer Patients during the COVID-19 Pandemic.

Telehealth is the delivery of many health care services and technologies to individuals at different geographical areas and is categorized as asynchronously or synchronously. The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions in health care delivery to breast cancer (BCa) patients and there is increasing demand for telehealth services. Globally, telehealth has become an essential means of communication between patient and health care provider. The application of telehealth to the treatment of BCa patients is evolving and increasingly research has demonstrated its feasibility and effectiveness in improving clinical, psychological and social outcomes. Two areas of telehealth that have significantly grown in the past decade and particularly since the beginning of the COVID-19 pandemic are telerehabilitation and teleoncology. These two technological systems provide opportunities at every stage of the cancer care continuum for BCa patients. We conducted a literature review that examined the use of telehealth services via its various modes of delivery among BCa patients particularly in areas of screening, diagnosis, treatment modalities, as well as satisfaction among patients and health care professionals. The advantages of telehealth models of service and delivery challenges to patients in remote areas are discussed.

Pathologic Factors Affecting Colorectal Cancer Survival in a Jamaican Population-the UHWI Experience.

OBJECTIVE: Colorectal carcinoma (CRC) is the third most common cancer and a leading cause of cancer-related deaths in Jamaica. Globally, CRC mortality rates have been decreasing in developed countries; however, CRC mortality rates are trending upwards in low-income or developing countries. Our objectives are to estimate the overall 5-year survival and to determine the pathologic factors associated with overall survival of colorectal adenocarcinoma after surgery at the University Hospital of the West Indies (UHWI). METHODS: Retrospective, observational (cross-sectional) study on CRC patients. We summarized and analyzed demographic, clinical data, histopathological data, and survival rates. Single predictor Cox regression models were used to establish associations between survival and specified clinicopathological characteristics. RESULTS: A total of 217 patients who underwent operative resection of colorectal adenocarcinoma from January 2004 to December 2013. Median survival time post-therapeutic intervention was 48 months. Late stage at diagnosis, positive circumferential resection margins, neural and vascular invasion, as well as three or more nodal metastases were all associated with statistically significant worsened outcome. CONCLUSIONS: Despite surgical quality meeting USA standards, CRC survival rates in Jamaica are 13% lower than survival of CRC in non-Hispanic Blacks in the USA. The survival trends found by our study support the application of international indices for CRC prognostication to Jamaican patients.

Effects of combined inositol hexakisphosphate and inositol supplement on antioxidant activity and metabolic enzymes in the liver of streptozotocin-induced type 2 diabetic rats.

Diabetes mellitus is associated with elevated reactive oxygen species, lipid abnormalities, reduced antioxidant activity and organ damage. This study examines the effects of combined inositol hexakisphosphate (IP6) and inositol supplement on antioxidant levels and other biochemical parameters in the liver of type 2 diabetic rats. Five groups of Sprague-Dawley rats were studied. Six rats were fed normal diet (non-diabetic control), while 24 rats were fed high-fat diet (HFD) for 4 weeks. Diabetes was induced in 18 of the rats fed HFD by intraperitoneal administration of streptozotocin. The diabetic rats were separated into three groups namely: combined IP6 and inositol, glibenclamide and diabetic control. The non-diabetic group fed high-fat diet was classified as a high-fat control group. For the final four weeks of the experiment, all rats were fed normal diet and given their respective treatment regimes. Hepatic antioxidant status, metabolic enzyme activity, lipid profile, peroxidative damage and liver histology, as well as, serum aminotransferase and alkaline phosphatase activities, and total bilirubin concentration were assessed. Treatment with combined IP6 and inositol supplement significantly increased liver reduced glutathione and high-density lipoprotein levels while liver triglyceride levels and serum alkaline phosphatase activity were significantly reduced by 27%, 50%, 38.5%, and 69.2% respectively compared to the diabetic control. Hepatic superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase activities were significantly upregulated by 55%, 26% and 53% respectively in the diabetic rats treated with combined IP6 and inositol compared to the diabetic control. Combined IP6 and inositol treatment resulted in the preservation of liver cell integrity and improved antioxidant status in type 2 diabetic rats.

Persistence of hepatic fibrosis in pediatric intestinal failure patients treated with intravenous fish oil lipid emulsion.

BACKGROUND: Pediatric intestinal failure (PIF) is a life-altering chronic condition with significant morbidity and mortality. Omegaven® therapy has been used to treat children with advanced intestinal failure associated liver disease. Our objective was to determine the evolution of hepatic fibrosis in PIF patients who received Omegaven® and describe their clinical outcome. METHODS: A retrospective review in PIF patients who received Omegaven® was performed. Patients were included if they had liver biopsies completed before Omegaven® therapy and after resolution of hyperbilirubinemia. Biopsy results were evaluated to determine the degree of fibrosis, inflammation, and cholestasis. Clinical and biochemical data was collected. RESULTS: Six patients were identified. Assessment of fibrosis at last follow-up demonstrated improvement in 2 patients and progression or stable fibrosis in 4/6. All patients demonstrated reduction in cholestasis and inflammation. One patient received a liver/intestine transplant and a second is listed, both of them with progressive fibrosis. One patient achieved full enteral nutrition, while the rest remain partially parenteral nutrition dependent. CONCLUSION: Use of Omegaven® is associated with reduced cholestasis and inflammation, but with persistence or worsening of fibrosis in some patients. A subset of patients with progressive fibrosis may develop portal hypertension and progressive liver disease.

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation.

Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that flank a histidine-rich region (HRR), and a C-terminal domain. To date, structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93 Å resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain, forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a 5-stranded antiparallel ß-sheet wrapped around a 5-turn α-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the antiangiogenic cleavage product from HRG.