The need for research targeting the link between occupational carcinogens and hepatopancreatobiliary cancers in Africa: A systematic review.

INTRODUCTION: Hepatopancreatobiliary (HPB) cancers encompassing malignancies of the liver, pancreas, gall bladder, and bile ducts pose a significant health burden in Africa. While the association of certain occupational carcinogens in cancer is well established globally, their potential role in HPB cancers remains understudied, especially in an African context. AIM: This systematic review delves into the association between occupational carcinogens and HPB cancer in Africa. It examines the current state of research on occupational carcinogens and HPB cancers in Africa, identifying key challenges and knowledge gaps. METHODS: This systematic review examined publications (published between 01 January 2012 and 31 May 2023) that highlight occupational carcinogens and HBP cancers in Africa. The search was conducted on electronic databases namely PubMed, Web of Science, and Africa Wide Information. RESULT: Due to the lack of information on the association between occupational carcinogens and HPB cancers in Africa, as a result of the paucity of published studies, only four articles were included in this study. Hepatocellular carcinoma (HCC) was the predominant cancer associated with the occupational carcinogen, aflatoxin. Agricultural workers, especially those involved in the production and processing of maize and peanuts, appear to be the most exposed to aflatoxin. CONCLUSION: Despite the sample size limitations due to the paucity of research studies on occupational carcinogens and HPB cancers in Africa, this study provides a reasonable tool for subsequent epidemiological studies. There is a need for more research on the association of occupational carcinogens and HPB cancers in Africa, especially with the growing industrialization.

Determining the Minimum Dataset for Surgical Patients in Africa: A Delphi Study.

BACKGROUND: It is often difficult for clinicians in African low- and middle-income countries middle-income countries to access useful aggregated data to identify areas for quality improvement. The aim of this Delphi study was to develop a standardised perioperative dataset for use in a registry. METHODS: A Delphi method was followed to achieve consensus on the data points to include in a minimum perioperative dataset. The study consisted of two electronic surveys, followed by an online discussion and a final electronic survey (four Rounds). RESULTS: Forty-one members of the African Perioperative Research Group participated in the process. Forty data points were deemed important and feasible to include in a minimum dataset for electronic capturing during the perioperative workflow by clinicians. A smaller dataset consisting of eight variables to define risk-adjusted perioperative mortality rate was also described. CONCLUSIONS: The minimum perioperative dataset can be used in a collaborative effort to establish a resource accessible to African clinicians in improving quality of care.

Chemokine receptor 8 expression may be linked to disease severity and elevated interleukin 6 secretion in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disease, which presents with epigastric pain and is clinically diagnosed by amylase and lipase three times the upper limit of normal. The 2012 Atlanta classification stratifies the severity of AP as one of three risk categories namely, mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP). Challenges in stratifying AP upon diagnosis suggest that a better understanding of the underlying complex pathophysiology may be beneficial. AIM: To identify the role of the chemokine receptor 8 (CCR8), expressed by T-helper type-2 Lymphocytes and peritoneal macrophages, and its possible association to Interleukin (IL)-6 and AP stratification. METHODS: This study was a prospective case-control study. A total of 40 patients were recruited from the Chris Hani Baragwanath Academic Hospital and the Charlotte Maxeke Johannesburg Academic Hospital. Bioassays were performed on 29 patients (14 MAP, 11 MSAP, and 4 SAP) and 6 healthy controls as part of a preliminary study. A total of 12 mL of blood samples were collected at Day (D) 1, 3, 5, and 7 post epigastric pain. Using multiplex immunoassay panels, real-time polymerase chain reaction (qRT-PCR) arrays, and multicolour flow cytometry analysis, immune response-related proteins, genes, and cells were profiled respectively. GraphPad Prism™ software and fold change (FC) analysis was used to determine differences between the groups. P<0.05 was considered significant. RESULTS: The concentration of IL-6 was significantly different at D3 post epigastric pain in both the MAP group and MSAP group with P = 0.001 and P = 0.013 respectively, in a multiplex assay. When a FC of 2 was applied to identify differentially expressed genes using RT2 Profiler, CCR8 was shown to increase steadily with disease severity from MAP (1.33), MSAP (38.28) to SAP (1172.45) median FC. Further verification studies using RT-PCR showed fold change increases of CCR8 in MSAP and SAP ranging from 1000 to 1000000 times when represented as Log10, compared to healthy control respectively at D3. The findings also showed differing lymphocyte and monocyte cell frequency between the groups. With monocyte population frequency as high as 70% in MSAP at D3. CONCLUSION: The higher levels of CCR8 and IL-6 in the severe patients and immune cell differences compared to MAP and controls provide an avenue for exploring AP stratification to improve management.

Serum Metabolomic and Lipoprotein Profiling of Pancreatic Ductal Adenocarcinoma Patients of African Ancestry.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman's correlation and Kapan Meier tests were conducted for correlation and survival analyses, respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose and lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used to predict patient survival and inform treatment intervention.

Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance.

Pancreatic cancer is one of the most deadly cancers, ranking amongst the top leading cause of cancer related deaths in developed countries. Features such as dense stroma microenvironment, abnormal signaling pathways, and genetic heterogeneity of the tumors contribute to its chemoresistant characteristics. Amongst these features, growth factors have been observed to play crucial roles in cancer cell survival, progression, and chemoresistance. Here we review the role of the individual growth factors in pancreatic cancer chemoresistance. Importantly, the interplay between the tumor microenvironment and chemoresistance is explored in the context of pivotal role played by growth factors. We further describe current and future potential therapeutic targeting of these factors.

Development of a Clinical Prediction Model for In-hospital Mortality from the South African Cohort of the African Surgical Outcomes Study.

BACKGROUND: Data on the factors that influence mortality after surgery in South Africa are scarce, and neither these data nor data on risk-adjusted in-hospital mortality after surgery are routinely collected. Predictors related to the context or setting of surgical care delivery may also provide insight into variation in practice. Variation must be addressed when planning for improvement of risk-adjusted outcomes. Our objective was to identify the factors predicting in-hospital mortality after surgery in South Africa from available data. METHODS: A multivariable logistic regression model was developed to identify predictors of 30-day in-hospital mortality in surgical patients in South Africa. Data from the South African contribution to the African Surgical Outcomes Study were used and included 3800 cases from 51 hospitals. A forward stepwise regression technique was then employed to select for possible predictors prior to model specification. Model performance was evaluated by assessing calibration and discrimination. The South African Surgical Outcomes Study cohort was used to validate the model. RESULTS: Variables found to predict 30-day in-hospital mortality were age, American Society of Anesthesiologists Physical Status category, urgent or emergent surgery, major surgery, and gastrointestinal-, head and neck-, thoracic- and neurosurgery. The area under the receiver operating curve or c-statistic was 0.859 (95% confidence interval: 0.827-0.892) for the full model. Calibration, as assessed using a calibration plot, was acceptable. Performance was similar in the validation cohort as compared to the derivation cohort. CONCLUSION: The prediction model did not include factors that can explain how the context of care influences post-operative mortality in South Africa. It does, however, provide a basis for reporting risk-adjusted perioperative mortality rate in the future, and identifies the types of surgery to be prioritised in quality improvement projects at a local or national level.

Role of different immune cells and metabolic pathways in modulating the immune response in pancreatic cancer (Review).

Pancreatic cancer is an aggressive cancer, making it a leading cause of cancer­related deaths. It is characteristically resistant to treatment, which results in low survival rates. In pancreatic cancer, immune cells undergo transitions that can inhibit or promote their functions, enabling treatment resistance and tumor progression. These transitions can be fostered by metabolic pathways that are dysregulated during tumorigenesis. The present review aimed to summarize the different immune cells and their roles in pancreatic cancer. The review also highlighted the individual metabolic pathways in pancreatic cancer and how they enable transitions in immune cells. Finally, the potential of targeting metabolic pathways for effective therapeutic strategies was considered.

SWATH-MS based proteomic profiling of pancreatic ductal adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways.

Pancreatic cancer accounts for 2.8% of new cancer cases worldwide and is projected to become the second leading cause of cancer-related deaths by 2030. Patients of African ancestry appear to be at an increased risk for pancreatic ductal adenocarcinoma (PDAC), with more severe disease and outcomes. The purpose of this study was to map the proteomic and genomic landscape of a cohort of PDAC patients of African ancestry. Thirty tissues (15 tumours and 15 normal adjacent tissues) were obtained from consenting South African PDAC patients. Optimisation of the sample preparation method allowed for the simultaneous extraction of high-purity protein and DNA for SWATH-MS and OncoArray SNV analyses. We quantified 3402 proteins with 49 upregulated and 35 downregulated proteins at a minimum 2.1 fold change and FDR adjusted p-value (q-value) ≤ 0.01 when comparing tumour to normal adjacent tissue. Many of the upregulated proteins in the tumour samples are involved in extracellular matrix formation (ECM) and related intracellular pathways. In addition, proteins such as EMIL1, KBTB2, and ZCCHV involved in the regulation of ECM proteins were observed to be dysregulated in pancreatic tumours. Downregulation of pathways involved in oxygen and carbon dioxide transport were observed. Genotype data showed missense mutations in some upregulated proteins, such as MYPN, ESTY2 and SERPINB8. Approximately 11% of the dysregulated proteins, including ISLR, BP1, PTK7 and OLFL3, were predicted to be secretory proteins. These findings help in further elucidating the biology of PDAC and may aid in identifying future plausible markers for the disease.

Hepatitis B virus-associated hepatocellular carcinoma in South Africa in the era of HIV.

BACKGROUND: Patients co-infected with hepatitis B virus (HBV) and the human immunodeficiency virus (HIV) are at risk of developing hepatocellular carcinoma (HCC). In sub-Saharan Africa, the overlap between high HIV and HBV prevalence may increase the incidence of HCC. This study investigated the impact of HBV/HIV co-infection on age at presentation and survival of HCC. METHODS: Ethical approval was obtained to recruit, following informed written consent, patients diagnosed with HCC at oncology units at four South African hospitals. Between December 2012 and August 2015, patients newly diagnosed with HCC were recruited and provided demographic and clinical data and blood specimens. Patients were tested for HBV, hepatitis C virus (HCV) and HIV. Survival data was available for a subset of patients. RESULTS: Of 107 HCC cases, 83 (78%) were male. Median age was 46 years (range 18 to 90 years), 68/106 (64%) were HBsAg-positive, and 22/100 (22%) were HIV infected. Among HBV surface antigen (HBsAg)-positive HCC cases, 18/66 (27%) were HIV-infected compared to 3/34 (9%) among those that were HBsAg-negative (p = 0.04). A greater proportion of HBV/HIV co-infected cases were female than HBV mono-infected (6/18, 33% vs 6/47, 13%; p = 0.005). In addition, HBV/HIV co-infected females presented at a younger mean age (36.8 years) than HBV mono-infected women (50.5 years) (p = 0.09). Median survival was 82 days among the HIV-infected HCC patients compared to 181 days among those without HIV (p = 0.15). CONCLUSIONS: HCC is an important complication in the HIV/HBV infected patient. HIV-positive patients presented with HCC at a younger age than HIV-negative patients, this effect appears to be greater in women. These data provide more evidence supporting the call to address. HCC as a cause of morbidity and mortality in the HBV/HIV co-infected patient population. (281 words).

Immunotherapeutic strategies in pancreatic ductal adenocarcinoma (PDAC): current perspectives and future prospects.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest human malignancies with a dismal prognosis. During PDAC progression, the immune response is affected as cancer cells evade detection and elimination. Recently, there have been advances in the treatment of PDAC using immunotherapy, although a lot more work is yet to be done. In this review, we discuss these advances, challenges and potentials. We focus on existing and potential immune targets for PDAC, drugs used to target them, and some clinical trials conducted so far with them. Finally, novel targets in the tumour microenvironment such as stromal cells and other potential future areas to explore including bacterial therapy and the use of neoantigens in immunotherapy are highlighted.

Relationship between low-density lipoprotein cholesterol and severe acute pancreatitis ("the lipid paradox").

BACKGROUND AND AIM: The aim of this study was to investigate the association between low-density lipoprotein cholesterol (LDL-C) and the development of severe acute pancreatitis (SAP). PATIENTS AND METHODS: A total of 674 patients with acute pancreatitis were enrolled. Non-linearity in the relationship between LDL-C and SAP was assessed by restricted cubic spline analysis. Univariable and multivariable regression analyses were used to identify independent risk factors of SAP. RESULTS: The restricted cubic spline analysis suggested a nonlinear association between high-density lipoprotein cholesterol (HDL-C), LDL-C and triglyceride levels and incidence of SAP. The incidence of SAP in patients with low LDL-C (<90 mg/dL), moderate LDL-C (90-150 mg/dL) and high LDL-C (>150 mg/dL) levels was 15.1%, 3.7% and 9.8%, respectively. Multivariable analysis confirmed that low LDL-C levels (odds ratio [OR] 3.05; 95% confidence interval [CI] 1.35-6.90), high LDL-C levels (OR 4.42; 95% CI 1.41-13.87) and low HDL-C levels (OR 6.90; 95% CI 2.61-18.23) but not high triglyceride levels (OR 1.05; 95% CI 0.40-2.72) were associated with the development of SAP. CONCLUSION: Both low LDL-C (<90 mg/dL) and high LDL-C (>150 mg/dL) levels within 24 hours from admission are independently associated with an increased risk of SAP.

Informal Caregiver Challenges for Advanced Cancer Patients During End-of-Life Care in Johannesburg, South Africa and Distinctions Based on Place of Death.

CONTEXT: In sub-Saharan Africa, late diagnosis with cancer is common. Many dying patients rely on family members for care; little is known about the challenges African informal caregivers face. OBJECTIVES: To better understand the challenges of informal caregivers at the end of life in South Africa, both at home and in inpatient facilities. METHODS: We included advanced cancer patients and caregivers from a public hospital in Johannesburg, South Africa. Study nurses interviewed patients and caregivers about their experiences. Using univariate and multivariate analyses, we determined the factors associated with greater caregiver difficulty, focusing on patients dying at home vs. in inpatient facilities. RESULTS: Among 174 informal caregivers, 62 (36%) reported "a lot" of challenges. These caregivers struggled most with keeping the patient clean (16%) and with patient interactions (34%). Symptoms associated with greater difficulty included pain (odds ratio [OR] 2.4 [95% CI 1.2-4.7]), urinary incontinence (OR 2.3 [95% CI 1.1-4.9]), fecal incontinence (OR 2.4 [95% CI 1.0-5.7]), insomnia (OR 2.9 [95% CI 1.3-6.9]), fatigue (OR 6.3 [95% CI 1.8-21.6]), extremity weakness (OR 2.9 [95% CI 1.3-6.9]), shame (OR 4.2 [95% CI 1.5-12.0]), and sadness (OR 2.3 [95% CI 1.1-4.8]). Caregivers of patients dying at home reported the greatest difficulty with patients' physical symptoms; caregivers of those dying in facilities reported the greatest difficulty with emotional symptoms. CONCLUSION: Informal caregivers of patients dying at home reported challenges with practical functional care; this effect was reduced in the inpatient setting. Skills training for these caregivers could relieve some of this burden.

Polymerase chain reaction amplifying mycobacterial DNA from aspirates obtained by endoscopic ultrasound allows accurate diagnosis of mycobacterial disease in HIV-positive patients with abdominal lymphadenopathy.

Abdominal lymphadenopathy in human immunodeficiency virus (HIV) infection remains a diagnostic challenge. We performed a prospective cohort study by recruiting 31 symptomatic HIV + patients with abdominal lymphadenopathy and assessing the diagnostic yield of endoscopic ultrasound fine-needle aspiration (EUS-FNA). Mean age was 38 years; 52% were female; and mean CD4 count and viral load were 124 cells/µL and 4 log, respectively. EUS confirmed additional mediastinal nodes in 26%. The porta hepatis was the most common abdominal site. Aspirates obtained by EUS-FNA were subjected to cytology, culture and polymerase chain reaction (PCR) analysis. Mycobacterial infections were confirmed in 67.7%, and 31% had reactive lymphadenopathy. Cytology and culture had low sensitivity, whereas PCR identified 90% of mycobacterial infections. By combining the appearance of aspirates obtained by EUS-FNA and cytologic specimens, we developed a diagnostic algorithm to indicate when analysis with PCR would be useful. PCR performed on material obtained by EUS-FNA was highly accurate in confirming mycobacterial disease and determining genotypic drug resistance.

Endocoil placement after endoscopic ultrasound-guided biliary drainage may prevent a bile leak.

AIM: To further reduce the risk of bleeding or bile leakage. METHODS: We performed endoscopic ultrasound guided biliary drainage in 6 patients in whom endoscopic retrograde cholangiopancreatography (ERCP) had failed. Biliary access of a dilated segment 2 or 3 duct was achieved from the stomach using a 19G needle. After radiologically confirming access a guide wire was placed, a transhepatic tract created using a 6 Fr cystotome followed by balloon dilation of the stricture and antegrade metallic stent placement across the malignant obstruction. This was followed by placement of an endocoil in the transhepatic tract. RESULTS: Dilated segmental ducts were observed in all patients with the linear endoscopic ultrasound scope from the proximal stomach. Transgastric biliary access was obtained using a 19G needle in all patients. Biliary drainage was achieved in all patients. Placement of an endocoil was possible in 5/6 patients. All patients responded to biliary drainage and no complications occurred. CONCLUSION: We show that placing endocoils at the time of endoscopic ultrasound guided biliary stenting is feasible and may reduce the risk of bleeding or bile leakage.

Gall bladder injuries as part of the spectrum of civilian abdominal trauma in South Africa.

BACKGROUND: Trauma to the gall bladder is rare, but when missed or improperly managed it may be associated with significant morbidity. The aim of the present study was to review the management and outcomes of gall bladder trauma in a trauma centre. METHODS: Forty-three patients with gall bladder injury due to abdominal trauma were reviewed over a 3-year period. Surgical management, associated injuries, morbidity and mortality rates were determined. RESULTS: Among 1242 patients undergoing laparotomy for acute trauma, 43 patients (3.46%) with gall bladder injuries were identified. Forty patients sustained penetrating injuries (37 with gunshot wounds and three with stab wounds), and three patients suffered from blunt trauma. All patients with gall bladder injury underwent abdominal exploration because of associated intra-abdominal injuries. Thirty-six patients were treated with cholecystectomy, four patients underwent primary suture repair of the gall bladder perforation, while three patients with gall bladder injury were treated without any surgical intervention at laparotomy. No complications could be attributed to the gall bladder trauma or surgery. CONCLUSION: Cholecystectomy is the preferred procedure of choice for gall bladder injuries and is associated with no morbidity.

An analysis of 124 surgically managed brachial artery injuries.

BACKGROUND: A 3-year review of surgically managed brachial artery injuries is presented. METHODS: The medical records were analyzed for demographic data, mechanism of injury, associated injuries, treatment, and outcome. RESULTS: There were 113 males and 11 females with a mean age of 28.7 years. The majority of the injuries were caused by stab and gunshot wounds in 57.3% and 29%, respectively. Primary anastomosis was possible in 47 patients, whereas 73 patients required vein interposition grafting. Lower arm fasciotomy was performed in 15 patients (12.1%). Associated injuries included peripheral nerve lesions in 77 (62.1%), nonpaired brachial vein injuries in 17 (13.7%), and concomitant humerus fracture in 12 (9.7%) patients. Thirty-nine patients (31.5%) had remote injuries. CONCLUSIONS: The primary repair of penetrating brachial artery injuries was possible in approximately one third of the patients. Approximately two thirds of the patients had associated nerve lesions. Critical limb ischemia rarely occurred.