A 10-year retrospective study of lung cancer in Uganda.

BACKGROUND: Lung cancer is a leading cause of cancer-related deaths in Uganda. In this study, we aimed to describe the baseline characteristics and survival of patients with lung cancer at the Uganda Cancer Institute (UCI). METHODS: We retrospectively reviewed medical records of all patients with a histological diagnosis of lung cancer registered at UCI between January 2008 and August 2018. Data on demographic, clinical, and treatment characteristics, and vital status were abstracted and analyzed. Patients with undocumented vital status on the medical records were contacted through phone calls. We determined survival as time from histological diagnosis to death. The Kaplan-Meier survival analysis was performed to estimate the median survival time and the 5-year overall survival rate. RESULTS: Of the 207 patients enrolled, 56.5% (n = 117) were female, median age was 60 years (range: 20-94), 78.7% (n = 163) were never-smokers and 18 (8.7%) were living with HIV. Presumptive anti-tuberculosis treatment was given to 23.2% (n = 48). Majority had non-small cell lung cancer (96.6%, n = 200) with 74.5% (n = 149) adenocarcinoma and 19% (n = 38) squamous cell carcinoma. All had advanced (stage III or IV) disease with 96.1% (n = 199) in stage IV. Chemotherapy (44.9%, n = 93) and biological therapy (34.8%, n = 72) were the commonest treatments used. Overall survival at 6 months, 1-, 2- and 5-years was 41.7, 29.7, 11.8, and 1.7%, respectively. The median survival time of 4.4 months was not statistically significantly different between participants with NSCLC or SCLC (4.5 versus 3.9 months, p = .335). CONCLUSION: In Uganda, adenocarcinoma is the predominant histologic subtype of lung cancer and patients are predominantly females, and non-smokers. Patients present late with advanced disease and poor overall survival. Public awareness should be heightened to facilitate early detection and improve outcomes.

Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation.

Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI-101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC-secreted factor activity that was associated with anti-inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI-101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.

Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy.

Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. We have constructed a recombinant protein named anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability. Anti-EGFR-iRGD, which targets EGFR and αvß3, spreads extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines, multicellular spheroids, and mice. Moreover, anti-EGFR-iRGD could improve anticancer drugs, such as doxorubicin (DOX), bevacizumab, nanoparticle permeability and efficacy in multicellular spheroids. This study draws attention to the importance of iRGD peptide in the therapeutic approach of anti-EGFR-iRGD. As a consequence, anti-EGFR-iRGD could be a drug candidate for cancer treatment and a useful adjunct of other anticancer drugs.

Does ventral hernia defect length, width, or area predict postoperative quality of life? Answers from a prospective, international study.

BACKGROUND: The goal of this study was to determine if ventral hernia defect length, width, or area predict postoperative pain and quality of life following ventral hernia repair (VHR). METHODS: The International Hernia Mesh Registry, a prospective database from 40 institutions worldwide, was queried for patients undergoing VHR from October 2007 to June 2012. Laparoscopic and open VHR were evaluated separately. Width and length were stratified into large, ≥10 cm and small, <10 cm, along with area as large, ≥100 cm(2) and small, <100 cm(2). RESULTS: In total, 865 International Hernia Mesh Registry patients underwent VHR. Large defect width, length, and area had no association with hernia recurrence or reoperation in both open and laparoscopic VHR. There was a significant increase in operating room time and length of stay for large compared with small width, length, and area for open and laparoscopic VHR patients (P < 0.05). Large area was associated with increased seroma and ileus in open and laparoscopic VHR (P < 0.05). There was greater pain and activity limitation at 1 mo for large versus small width and area whether repaired laparoscopically or open (P < 0.05). When comparing large to small length, there was no difference in pain for all follow-up time points when repaired laparoscopically, but there is significantly increased odds of pain and activity limitation at 1, 6, and 12 mo when repaired open (P < 0.05). CONCLUSIONS: Patients undergoing laparoscopic or open VHR with large defect widths and total area have a greater chance of pain and activity limitation at 1-mo follow-up, but not long term. Large defect lengths are associated with increased early and chronic discomfort in open VHR only.

Sevelamer restores bone volume and improves bone microarchitecture and strength in aged ovariectomized rats.

Sevelamer hydrochloride, a noncalcium phosphate binder, has been shown to reduce coronary artery and aortic calcification, and to improve trabecular bone mineral density in hemodialysis patients with chronic kidney disease. Here, we examined whether sevelamer given orally for 12 wk with normal food could restore bone volume (BV) and strength in aged ovariectomized (OVX) rats starting at 4 wk after OVX. Dual-energy x-ray absorptiometry, microcomputerized tomography, and bone histomorphometry analyses showed that OVX animals receiving sevelamer had increased trabecular BV (51%), trabecular number (43%), trabecular thickness (9%), cortical thickness (16%), mineral apposition rate (103%), bone formation rate (25%), and enhanced cortical and trabecular bone mechanical strength as compared with OVX rats. Sevelamer decreased collagen C telopeptide, increased osteocalcin levels, and decreased phosphate and magnesium levels without affecting calcium levels in the blood. Although sevelamer was not absorbed systemically, it stimulated osteoblast differentiation in BM-derived mesenchymal stem cell cultures, as evaluated by alkaline phosphatase positive colony-forming units, and inhibited recombinant human soluble receptor activator of nuclear factor-kappaB ligand-induced osteoclast differentiation, as evaluated by tartrate-resistant acid phosphatase positive cells in bone mineral-hematopoietic stem cell cultures. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis revealed that 69 proteins were differently expressed after OVX, of which 30% (20 of 69) were reversed to sham activity after sevelamer intake. PTH, fibroblast growth factor-23, and cytokine profile in serum were not significantly changed. Together, these results suggest that sevelamer in food increases the BV and improves biomechanical properties of bone in OVX rats.

Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors.

BACKGROUND: Coronary artery calcification is a common feature of atherosclerosis, occurring in 90% of angiographically significant lesions. There is recent evidence that coronary artery calcification is frequent in hemodialysis patients and it has been suggested that this increased incidence may be associated to uremia-related factors. The development and progression of coronary artery calcification is similar to osteogenesis. The aim of this study was to evaluate the relationship between coronary artery calcification, uremia-related factors, and bone histomorphometry in hemodialysis patients. METHODS: A total of 101 hemodialysis patients were assessed for biochemical markers of inflammation, oxidative stress, and bone metabolism. Subsequently, they were submitted to multislice coronary tomography (MSCT) and transiliac bone biopsy. RESULTS: The median calcium score was 116.2 (range 0 to 5547). Fifty-two percent of the patients showed moderate and severe coronary artery calcification, 20% had calcium scores greater than 1000. In univariate analysis, age (r= 0.57, P < 0.000001), osteoprotegerin (OPG) (r= 0.44, P= 0.00002), and body mass index (BMI) (r= 0.24, P= 0.01) correlated positively with calcium score. Bone trabecular volume and trabecular thickness correlated negatively with calcium score (r=-0.24, P= 0.02; r=-0.22, P= 0.03). There was a correlation of borderline significance between calcium score and C-reactive protein (CRP) (r= 0.18, P= 0.062). The multiple linear regression analysis identified OPG as the only variable independently associated with coronary artery calcification. CONCLUSION: Coronary artery calcification is highly prevalent in the hemodialysis population and is associated with older age, higher BMI, inflammation and reduced trabecular bone volume. Higher OPG is independently associated with coronary artery calcification and may represent an incomplete self-defensive response to the progression of atherosclerosis in hemodialysis patients.

Meeting increased demand.

New Zealand is a little country with a little economy but with a population that's rapidly aging. New Zealand's population is only 4.3 million people. It's GDP is only $US58.6 billion (2002). New Zealand's expenditure on health as a percentage of GDP is not out of line with that of other countries. As a nation we have been increasing expenditure on health over recent years. In 1990 we spent 7% of GDP on health. In 1995 that increased to 7.65% and is now 8.3%. However, in per capita terms our expenditure on health does not compare so well with like countries. The size of New Zealand's economy is restricting what our country spends on health. Health is already the second highest demand on the New Zealand tax dollar. The tolerance of New Zealanders would be challenged if a Government attempted to increase taxes further to meet the growing demands for expenditure on health, but at the same time the population's expectations are increasing. This is the challenging situation we face today. What lies ahead? Like all industrialized countries New Zealand is facing an aging population. The population below age 40 is decreasing, but it is increasing significantly over that age. 16% of the population is currently aged over 60. By 2051 this proportion will almost double to just over 31%. Coupled with the aging population is increased awareness and expectations, as access to options for treatment and technology becomes readily accessible to the population through such media as the internet. The extent of the impact of the aging population can be clearly represented by focusing on one specialty such as orthopaedics. The New Zealand Orthopaecic Association undertook a study in July 2003 which concluded (among other things) that as a result of the projected aging of the population, over the next 50 years: Musculo-skeletal operations will increase by over 30%. The number of hip replacements will nearly double. The incidence of osteoporosis will increase by a massive 201%. The number of people affected by arthritis will increase by nearly 50%. A huge increase in numbers affected with musculoskeletal conditions will require significant increases in health care resources, including hospital beds and facilities, orthopaedic surgeons and other health care professionals. New Zealand has been slow to acknowledge and plan for the increased demand for health services which is looming. Growing New Zealand's economy will help, but alone will not be enough. It is more than just finding the financial resources to better meet the demand. The enormous demands on the availability of treatment resources including hospital facilities and trained health care professionals must be addressed. There are major workforce issues to be faced. The change in population distribution between young and old will have an impact and it will be necessary to ensure that there are sufficient numbers of properly trained health care professionals available at all levels. It is hoped that improvements in preventative care programmes and new technologies and treatment techniques may reduce the rate of demand. As the health of our population is improved through targeted programmes dealing with obesity, diabetes, smoking and accident prevention, it may be possible to reallocate or change the focus of resources within the health and hospital sectors. Many countries are developing national strategies for their aging population. Clearly the New Zealand Government needs to move swiftly to develop a plan to manage the increased burden that is developing as a result of the aging population. That plan must create an environment which facilitates, encourages and supports greater private investment in healthcare facilities and healthcare delivery. Incentives must be created to motivate individuals to take greater responsibility for their healthcare needs and the funding of it. The development of a long term strategy to meet the challenges of the aging population is a priority.