Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes.

INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.

Fracture incidence and fracture-related mortality decreased with decreases in population mobility during the early days of the COVID-19 pandemic: an epidemiological study.

INTRODUCTION: We investigated the impact of coronavirus disease 2019 (COVID-19) social distancing measures on fracture incidence and fracture-related mortality, as well as associations with population mobility. METHODS: In total, 47 186 fractures were analysed across 43 public hospitals from 22 November 2016 to 26 March 2020. Considering the smartphone penetration of 91.5% in the study population, population mobility was quantified using Apple Inc's Mobility Trends Report, an index of internet location services usage volume. Fracture incidences were compared between the first 62 days of social distancing measures and corresponding preceding epochs. Primary outcomes were associations between fracture incidence and population mobility, quantified by incidence rate ratios (IRRs). Secondary outcomes included fracture-related mortality rate (death within 30 days of fracture) and associations between emergency orthopaedic healthcare demand and population mobility. RESULTS: Overall, 1748 fewer fractures than projected were observed during the first 62 days of COVID-19 social distancing (fracture incidence: 321.9 vs 459.1 per 100 000 person-years, P<0.001); the relative risk was 0.690, compared with mean incidences during the same period in the previous 3 years. Population mobility exhibited significant associations with fracture incidence (IRR=1.0055, P<0.001), fracture-related emergency department attendances (IRR=1.0076, P<0.001), hospital admissions (IRR=1.0054, P<0.001), and subsequent surgery (IRR=1.0041, P<0.001). Fracture-related mortality decreased from 4.70 (in prior years) to 3.22 deaths per 100 000 person-years during the COVID-19 social distancing period (P<0.001). CONCLUSION: Fracture incidence and fracture-related mortality decreased during the early days of the COVID-19 pandemic; they demonstrated significant temporal associations with daily population mobility, presumably as a collateral effect of social distancing measures.

Management of para-aortic lymph node metastasis in colorectal patients: A systemic review.

INTRODUCTION: Para-aortic lymph node (PALN) involvement occurs in up to 2% of colorectal cancer (CRC) patients. While resection for isolated hepatic and pulmonary metastases in colorectal cancer is standard practice, the role of PALN dissection (PALND) in CRC has not been established and remains a controversy. We aim to perform a systematic review of the literature to determine if extensive lymphadenectomy improves survival, and is an acceptable strategy for PALN metastasis (PALNM). MATERIALS AND METHODS: A systematic search of PubMed and Embase databases for studies reporting on patients with isolated PALNM in CRC was performed. Studies including patients with synchronous and metachronous PALN were included, and studies including patients with other metastases were excluded. RESULTS: Eighteen retrospective, single-centre studies were included in the final analysis. The reported incidence of isolated PALNM ranged from 1.3 to 1.7%. A total of 370 patients with PALNM were evaluated, of which 145 had synchronous, and 225 had metachronous PALNM. For synchronous PALNM, the 5-year overall survival (OS) after metastatectomy, ranged from 22.7% to 33.9%. For metachronous PALNM, the 5-year OS ranged from 15 to 60%; median OS was 34-40 months in the PALND versus 3-14 months for patients who did not undergo PALND. There were no reported surgery related mortalities, and overall surgical morbidity was 7.8-33%. CONCLUSION: PALND for isolated PALNM from colorectal cancer can be performed with minimal morbidity and confers a survival advantage, in comparison with conventional palliative chemotherapy or chemoradiation therapy.

Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial.

BACKGROUND: The purpose of the present study was to determine whether intrahepatic injection of (131)I-lipiodol (Lipiodol) is effective against recurrence of surgically resected hepatocellular carcinoma (HCC). METHODS: From June 2001 through March 2007, this nationwide multi-center prospective randomized controlled trial enrolled 103 patients 4-6 weeks after curative resection of HCC with complete recovery (52: Lipiodol, 51: Control). Follow-up was every 3 months for 1 year, then every 6 months. Primary and secondary endpoints were recurrence-free survival (RFS) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR). The design was based on information obtained from a similar trial that had been conducted in Hong Kong. RESULTS: The Lipiodol group showed a small, and nonsignificant, improvement over control in RFS (HR = 0.75; 95 % confidence interval [95 % CI] 0.46-1.23; p = 0.25) and OS (HR = 0.88; 95 % CI 0.51-1.51; p = 0.64). Only two serious adverse events were reported, both with hypothyroidism caused by (131)I-lipiodol and hepatic artery dissection during angiography. CONCLUSIONS: The randomized trial provides insufficient evidence to recommend the routine use of (131)I-lipiodol in these patients.

Randomized clinical trial of open hepatectomy with or without intermittent Pringle manoeuvre.

BACKGROUND: The intermittent Pringle manoeuvre (IPM) is commonly applied during liver resection. Few randomized trials have addressed its effectiveness in reducing blood loss and the results have been conflicting. The present study investigated the hypothesis that IPM could reduce blood loss during liver resection by 50 per cent. METHODS: Between May 2008 and April 2011, patients who underwent elective open hepatectomy were randomized into an IPM or no Pringle manoeuvre (NPM) group and stratified according to the presence or absence of cirrhosis. Data on demographics, type of hepatectomy, operative blood loss, duration of operation, mortality, morbidity and postoperative liver function were recorded and analysed. The primary endpoint was operative blood loss. RESULTS: There were 63 patients in each group. Median (range) operative blood loss was 370 (50-3600) ml in the IPM group versus 335 (40-3160) ml in the NPM group (P = 1·000). There were no differences in blood loss in different phases of the operation, blood loss per area of liver transected or blood transfusion rate, nor in total duration of operation or liver transection time. Postoperative serum alanine aminotransferase levels were higher in the IPM group (P < 0·001). There were more postoperative complications in the IPM group (41 versus 24 per cent; P = 0·036). CONCLUSION: The IPM did not reduce blood loss, but was associated with raised levels of postoperative liver parenchymal enzymes and more complications. REGISTRATION NUMBER: NCT00730743 (http://www.clinicaltrials.gov).

Diagnosis of tuberculous lymphadenitis using fine needle aspiration biopsy.

BACKGROUND: Tuberculous lymphadenitis is the commonest form of extrapulmonary tuberculosis. However, the optimal approach to diagnosis, employing biopsy by either fine needle aspiration (FNA) or surgical excision, remains uncertain. AIMS: To evaluate the diagnostic value of biopsy using each of the component diagnostic modalities of FNA (microscopy, cytology and culture), and compare these with excision biopsy in the diagnosis of tuberculous lymphadenitis in a predominantly migrant population in Melbourne. METHODS: A retrospective examination of tuberculous lymphadenitis cases presenting to Western Health over 12 years was conducted. Using a reference method of positive culture of Mycobacterium tuberculosis, the diagnostic sensitivities of each modality employed in FNA were determined. RESULTS: Forty-two subjects having FNA and 30 having excision biopsy as the initial investigation were compared. Among specimens obtained by FNA, sensitivity of microscopy was 18% (95% confidence interval (CI): 5­40%) and sensitivity of cytology was 38% (95% CI: 20­59%). For specimens obtained by excision biopsies, sensitivities for microscopy and histology were 17% (95% CI: 2­32%) and 96% (95% CI: 88­100%) respectively. Sensitivity of culture performed on FNA specimens was 86% (95% CI: 65­97%). CONCLUSIONS: Given the relatively high sensitivity of mycobacterial cultures from FNA, this study supports its routine use as the initial investigation in most patients with suspected tuberculous lymphadenitis. Microscopy and cytology add relatively little to the clinical utility of FNA

Polymyositis and dermatomyositis in Sarawak: a profile of patients treated in the Sarawak General Hospital.

We performed a cross-sectional study of the demography, clinical and laboratory features of patients with polymyositis and dermatomyositis followed up in our centre from 2006 to 2009. There were 12 cases, with the majority of them (58.3%) being woman. They have a mean age of 57.8 years and mean disease duration of 11.83 (SD 9.92) months. Our patients comprised of multi-ethnic groups with predominantly Chinese (83.3%), Sarawak natives (8.3%) and Malays (8.3%). They have a mean lag time to diagnosis of 3.67 (SD 4.27) months. Nine (75%) patients had dermatomyositis and 3(25%) had polymyositis. The common clinical manifestations found in our patients were proximal myopathy (100%), neck weakness (33.3%), dysphagia (33.3%) and interstitial lung disease (33.3%). For the nine patients with dermatomyositis, the most common dermatological manifestations were shawl sign (88.9%) and V sign (88.9%). Muscle enzymes were raised in 91.7% of patients. Electromyographies were carried out in four patients, and only one of our patients had muscle biopsy. Only 41.7% of our patients have positive ANA. The majority received prednisolone (100%) and hydroxychloroquine (58.3%). Malignancy occurred in five (three nasopharyngeal carcinomas, one sigmoid colon cancer and one lung cancer) out of the nine dermatomyositis patients but none in the polymyositis group. The mortality rate in our group was 4(33.3%) over the 4-year period. This study demonstrated the rarity of PM/DM in our centre with considerable lag time to diagnosis in our patients. Despite lack of muscle biopsy in our centre, our centre achieved appropriate diagnosis and management of PM/DM.

Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma.

BACKGROUND: The role of anti-viral therapy in prevention of hepatocellular carcinoma (HCC) recurrence is to be defined. AIM: To investigate the role of anti-viral therapy in prevention of tumour recurrence after curative treatment of hepatitis B virus (HBV)-related HCC. METHODS: A systematic electronic search on keywords including HCC and different anti-viral therapies was performed through eight electronic databases, including Medline, EMBASE and Cochrane Databases. The primary outcome was HCC recurrence after curative treatment of HBV-related HCC. The secondary outcomes were mortality related to HCC, mortality related to liver failure and the overall mortality. RESULTS: Nine cohort studies were included with a total number of 551 patients: 204 patients with anti-viral treatment group and 347 patients without anti-viral treatment (control group). There was significant difference in the incidence of HCC recurrence in favour of the anti-viral treatment group (55% vs. 58%; odds risk (OR)=0.59, 95% CI 0.35-0.97, P=0.04). The risk of HCC was reduced by 41% in the anti-viral treatment group. There were also significant differences in favour of anti-viral treatment group in terms of liver-related mortality (0% vs. 8%; OR=0.13, 95% CI 0.02-0.69, P=0.02) and overall mortality (38% vs. 42%; OR=0.27, 95% CI 0.14-0.50, P<0.001). CONCLUSIONS: Anti-viral therapy has potential beneficial effects after the curative treatment of HBV-related hepatocellular carcinoma in terms of tumour recurrence, liver-related mortality and overall survival. Anti-viral therapy should be considered after curative treatment of hepatocellular carcinoma.

The many faces of intraosseous haemangioma: a diagnostic headache.

Intraosseous haemangioma constitutes less than ten percent of all primary bone neoplasms. Approximately 75 percent occur in the calvarium or vertebrae, with long bones, short tubular bones and ribs constituting the rest. We describe a 52-year-old woman who presented with left knee pain for 4-5 years and loss of weight over one week. An initial radiograph of the knee showed several well circumscribed isodense lesions with sclerotic rims in the medullary cavity of the distal femur and diaphysis of the left tibia. There were also lucent lesions with a slightly sclerotic rim in the diaphysis of the left tibia and proximal left fibula. In view of the clinical presentation and radiological findings, extensive investigations were made to rule out metastases and multiple myeloma. An open biopsy with segmental osteotomy of the left mid fibular lesion revealed an intraosseous haemangioma.

Systemic sclerosis in Sarawak: a profile of patients treated in the Sarawak General Hospital.

We performed a cross-sectional study of the demography, clinical and laboratory features of patients with systemic sclerosis patients followed up in our centre from 1984 to 2007. There were 23 cases with the majority of them (96%) being female. They have a mean age of 50.3 years and a mean disease duration of 6.02 (SD 5.82) years. Our patients comprised of multi-ethnic groups with predominantly Chinese (52%), Sarawak natives (35%) and Malays (13%). They have a mean lag time to diagnosis of 24.8 (SD 34.8) months. All the patients have sclerodermatous skin changes with 16(70%) having diffuse scleroderma and 7(30%) having limited scleroderma. The common clinical manifestations found in our patients were Raynaud's phenomenon (91%), sclerodactyly (65%), digital ulcers (52%) and pulmonary fibrosis (52%). There was low incidence of pulmonary hypertension (13%) and renal involvement (4%). The majority of our patients (67%) have positive ANA with 33% positive Scl-70. The majority received calcium channel blockers (87%), aspirin (48%) and low-dose prednisolone (48%). One patient developed adenocarcinoma of the lung on follow-up. This study demonstrated the rarity of systemic sclerosis in our centre with considerable lag time to diagnosis in our patients. Diffuse cutaneous systemic scleroderma is more common in our centre with rare pulmonary hypertension and renal involvement.

Detection of the p53 response in zebrafish embryos using new monoclonal antibodies.

The zebrafish has many advantages as a vertebrate model organism and has been extensively used in the studies of development. Its potential as a model in which to study tumour suppressor and oncogene function is now being realized. Whilst in situ hybridization of mRNA has been well developed in this species to study gene expression, antibody probes are in short supply. We have, therefore, generated a panel of anti-zebrafish p53 monoclonal antibodies and used these to study the p53 response in zebrafish embryos. By immunohistochemistry, we show that the exposure of zebrafish embryos to p53-activating agents such as R-roscovitine and gamma-irradiation results in the accumulation of p53 protein in the gut epithelium, liver and pancreas. A combination of R-roscovitine and gamma-irradiation results in massive p53 induction, not only in the pharyngeal arches, gut region and liver but also in brain tissues. Induction of apoptosis and expression of p53 response genes are seen in regions that correspond to sites of p53 protein accumulation. In contrast, although zebrafish tp53(M214K) mutant embryos showed a similar accumulation of p53 protein, a complete lack of a downstream p53-dependent response was observed. In this system the p53 gene is identified as a p53-responsive gene itself. Our results demonstrate that zebrafish p53 protein can readily be induced in embryos and detected using these new antibody tools, which will increase the usefulness of zebrafish as a model in compound-based screening for novel drugs in cancer research.

Standard of care for type 2 diabetic patients in a public hospital general medical clinic: report of a self-audit.

We audited the standard of care provided to 200 consecutive type 2 diabetic patients attending our hospital general medical clinic. Data on diabetes related processes and outcome measures were collected. Annual testing rates (blood pressure 100%, fasting lipid profile 91.8%, HbA1c 69%) were higher compared to complications screening rates (Eye 69%, albuminuria 51%, foot 22.4%). Lifestyle intervention was lacking with BMI documented in 38.3% of patients and smoking history in 46%. Fifty percent and 41% of patients with HbA1c > 7.5% were referred to diabetes educator and dietitian respectively. For outcome measures, 26% of patients achieved HbA1c < or = 7%, 33% achieved BP < or = 130/80 while 56% achieved LDL < or = 2.6 mmol/L. Aspirin was prescribed in 78% and ACE inhibitor or angiotensin receptor blocker in 91.8% of patients. Lifestyle intervention and complication screening are the two major areas of deficiencies in the care of type 2 diabetic patients in our hospital general medical clinic.

Intracranial epidermoid cyst with hemorrhage: MR imaging findings.

We present a case of a 28-year-old woman with a cerebellopontine angle and prepontine cistern epidermoid cyst with unusual signal intensity. She presented with cranial nerve neuropathy and unsteady gait. MR imaging showed a tumor mass with central area of hemorrhage and a focal area of heterogeneous signal intensity with spotty enhancement, which correlated histologically to old blood in a cystic lumen and granulation of a cystic wall, with a large area of hemorrhage and mild vascularity.

A rare case of subretinal cysticercosis.

This is a case of a 25 year old lady whose eye had been infected by cysticercosis. This case highlighted that the inflammation was due to host immune response. She was treated with oral corticosteroid and the lesions regressed.

Glycaemic control of diabetic patients in an urban primary health care setting in Sarawak: the Tanah Puteh Health Centre experience.

Achieving glycaemic goals in diabetics has always been a problem, especially in a developing country with inadequate facilities such as in Sarawak in Malaysia. There are no reported studies on the control of diabetes mellitus in a diabetic clinic in the primary health care setting in Sarawak. This paper describes the profile of 1031 patients treated in Klinik Kesihatan Tanah Puteh Health Centre. The mean age was 59 years, the mean BMI 27 kg/m2. There was a female preponderance and mainly type-2 diabetes. Mean HbA1c was 7.4%. Glycaemic control was optimal in 28% (HbA1c <6.5%), fair in 34% (HbA1c 6.5-7.5%) and poor in 38% (HbA1c >7.5%). Reasonable glycaemic control can be achieved in the primary health care setting in Sarawak.

Systemic considerations in the management of diabetic retinopathy.

PURPOSE: To highlight the systemic factors which affect onset and/or progression of diabetic retinopathy (DR) and to emphasize the role and responsibilities of ophthalmologists and other eye care providers to ensure that appropriate systemic medical evaluation of the patient with diabetes is being pursued. DESIGN: Literature review of publications relevant to diabetic retinopathy, blood glucose control, diabetes mellitus type, hypertension, renal disease, elevated serum lipids, exercise, pregnancy, anticoagulation, thrombolysis, smoking, anemia and antioxidant ingestion. FINDINGS: Intensive blood glucose control and control of systemic hypertension reduce the risk of new onset DR and slow the progression of existing DR. Severe DR may be an indicator of renal disease while severe renal disease and its treatment can affect the progression of DR. Elevated serum lipids are associated with macular exudate and moderate visual loss. Certain types of excessive exercise in patients with advanced stages of retinopathy may aggravate vitreous hemorrhage. During pregnancy, DR should be monitored closely as transient progression of DR can occur. Therapeutic anticoagulation and thrombolysis are not contraindicated at any stage of DR. Anemia can result in progression of DR, smoking in general should be discouraged, and the role of antioxidant therapy requires further study. CONCLUSIONS: Blindness from diabetic retinopathy is now largely preventable with timely detection and appropriate interventional therapy. Routine, repetitive, lifelong, expert clinical retinal examination is essential for the fundamental ophthalmic care of the patient with diabetes. However, diabetes mellitus is a systemic disease and thus optimal ophthalmic care must include diligent evaluation and treatment of concomitant systemic disorders that influence the development, progression and ultimate outcome of diabetic retinopathy. Optimization of these systemic considerations through an intensive, multi-disciplinary, healthcare team-based approach will maximize the ophthalmic and general health of these patients. Ophthalmologists and other eye care providers are critical members of this team with unique responsibilities to ensure that appropriate systemic medical evaluation is being pursued.

Indocyanine green anterior segment angiography for studying conjunctival vascular changes after trabeculectomy.

BACKGROUND: The aim of the study was to evaluate the use of indocyanine green (ICG) for angiography of the anterior segment to characterize conjunctival and episcleral vasculature changes after trabeculectomy. METHODS: This was a prospective evaluation of anterior segment ICG angiography in 10 eyes of 10 patients undergoing trabeculectomy for the first time. Trabeculectomy was performed with intraoperative sponge application of 5-fluorouracil (5 cases) or mitomycin C (5 cases). Anterior segment ICG angiography was performed prior to surgery, then at 2 weeks and 2 months after surgery. RESULTS: With ICG, the anterior segment vessels were well delineated, including deep episcleral veins, which have not been clearly shown in previous angiographic techniques. Late phases of the angiogram could also be studied. The vascular alterations after trabeculectomy noted included oss of vascularity over the bleb area and vascular anastomoses along the perimeter of the avascular bleb. CONCLUSIONS: Angiography using ICG has potential as an investigative tool to study the conjunctival and episcleral vasculature changes after trabeculectomy.

Importance of local tumour control in breast cancer.

The overall importance of local tumour control in the management of breast cancer, specifically the influence of local control on survival, remains one of the fundamental questions for oncologists. This review addresses the issues surrounding local tumour control, including the evolution of the concept of disease spread, the rationale for local control, the results of studies of radiotherapy after breast-conserving surgery and after mastectomy, and an interpretation of the recent data on post-mastectomy radiotherapy.

Accuracy of clinical estimates of intraocular pressure in Chinese eyes.

PURPOSE: To investigate the validity of clinical estimates of intraocular pressure (IOP) in Chinese people. DESIGN: Prospective, cross-sectional, hospital-based in vivo study. PARTICIPANTS: Twenty-three ethnic Chinese adults (aged 35-82 years) undergoing routine phacoemulsification surgery were examined. TESTING: "True" IOP was measured with a solid-state hemodynamic monitor through a cannula in the anterior chamber. IOP was set successively to 10, 20, and 30 mmHg in each subject, using a reservoir of balanced salt solution. Intraocular pressure was simultaneously estimated by use of a hand-held applanation tonometer (Perkin's) and a Tono-Pen. The association between ocular biometric variables and measurement error was examined. MAIN OUTCOME MEASURES: The median of three readings at each IOP level was taken as the IOP estimate of each instrument. Measurement error was calculated as the mean difference (tonometer minus direct measurement). RESULTS: The error for the hand-held applanation tonometer was -1.6, -4.3 and -5.7 at 10, 20, and 30 mmHg, respectively. For the Tono-Pen the measurement error was +0.4, -2.0, and -4.1 at 10, 20, and 30 mmHg, respectively. We could identify no association between measurement error and corneal thickness or curvature, anterior chamber depth, or axial length. CONCLUSIONS: The applanation tonometer and Tono-Pen underestimate the true IOP in Chinese eyes. Error increases as true IOP increases. These tonometers do not give an accurate estimate of IOP in East Asians.

Role of vascular endothelial growth factor in diabetic vascular complications.

BACKGROUND: Much of the morbidity and mortality associated with diabetes mellitus predominantly reflects its deleterious effects on microcirculation and macrocirculation. During the past few years, rapid advancement has been made in our understanding of the mechanisms and molecules involved in the pathogenesis of diabetic microvasculopathy. This is particularly true with regard to retinal vascular disease and the role of the angiogenesis- and vasopermeability-inducing molecule, vascular endothelial growth factor (VEGF). METHODS: Biochemical studies in many relevant cell types have been performed. Effects of VEGF action and inhibition have been evaluated in animals. Interventions that block the biochemical pathways initiated by VEGF have been tested both in culture and in animals. Human clinical trials have begun. RESULTS: VEGF induces vascular endothelial cell proliferation, migration and vasopermeability in many cells and tissues. In vivo, VEGF has been identified as a primary initiator of proliferative diabetic retinopathy, and as a potential mediator of nonproliferative retinopathy. In addition, VEGF has been implicated in the development of neuropathy and nephropathy in the patient with diabetes. In patients with diabetes and coronary artery or peripheral vascular disease, VEGF may induce development of cardiac and limb vascular collateralization, respectively. Many biochemical processes mediating these actions have now been elucidated. CONCLUSIONS: VEGF appears to play a central role in mediating diabetic vasculopathy in many organs. Improved understanding of the molecular mechanisms underlying these processes has permitted development of novel therapeutic interventions, several of which are now in human clinical trials. These scientific advances and various implications for the future care of vasculopathy associated with diabetes will be discussed.