GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.

The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.

miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance.

The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.

Membranous Nectin-4 expression is a risk factor for distant relapse of T1-T2, N0 luminal-A early breast cancer.

Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.

Dual targeting of ErbB-2/ErbB-3 results in enhanced antitumor activity in preclinical models of pancreatic cancer.

ErbB-3 and its ligand NRG-1ß are key players in driving oncogenic signaling and resistance to therapy through the activation of the PI3K/Akt pathway. We have recently reported that EV20, a humanized anti-ErbB3 antibody, possesses a marked antitumor activity in a variety of human tumor models, including pancreatic cancer (PC). Here, we report that despite epidermal growth factor receptor overexpression, PC cells are more sensitive to NRG-1ß than EGF in terms of Akt activation and cell proliferation. Using stable ErbB-3-knocked down cells and EV20 in combination with trastuzumab, we showed that dual targeting of ErbB-2 and ErbB-3 was necessary to completely abrogate ErbB-3 signaling and to impair cell proliferation. Similarly, enhanced therapeutic efficacy of the antibody combination was seen in xenografts originating from K-Ras-mutated HPAF-II and SW1990 cells, without increasing the toxicity. These results indicate that dual targeting of ErbB-2 and ErbB-3 could represent a new therapeutic approach in PC.Oncogenesis (2014) 3, e117; doi:10.1038/oncsis.2014.31; published online 18 August 2014.

Randomised clinical trial: mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease--a double-blind, randomised, placebo-controlled study.

BACKGROUND: Placebo-controlled studies in maintaining remission of symptomatic uncomplicated diverticular disease (SUDD) of the colon are lacking. AIM: To assess the effectiveness of mesalazine and/or probiotics in maintaining remission in SUDD. METHODS: A multicentre, double-blind, placebo-controlled study was conducted. Two hundred and ten patients were randomly enrolled in a double-blind fashion in four groups: Group M (active mesalazine 1.6 g/day plus Lactobacillus casei subsp. DG placebo), Group L (active Lactobacillus casei subsp. DG 24 billion/day plus mesalazine placebo), Group LM (active Lactobacillus casei subsp. DG 24 billion/day plus active mesalazine), Group P (Lactobacillus casei subsp. DG placebo plus mesalazine placebo). Patients received treatment for 10 days/month for 12 months. Recurrence of SUDD was defined as the reappearance of abdominal pain during follow-up, scored as ≥5 (0: best; 10: worst) for at least 24 consecutive hours. RESULTS: Recurrence of SUDD occurred in no (0%) patient in group LM, in 7 (13.7%) patients in group M, in 8 (14.5%) patients in group L and in 23 (46.0%) patients in group P (LM group vs. M group, P = 0.015; LM group vs. L group, P = 0.011; LM group vs. P group, P = 0.000; M group vs. P group, P = 0.000; L group vs. P group, P = 0.000). Acute diverticulitis occurred in six group P cases and in one group L case (P = 0.003). CONCLUSION: Both cyclic mesalazine and Lactobacillus casei subsp. DG treatments, particularly when given in combination, appear to be better than placebo for maintaining remission of symptomatic uncomplicated diverticular disease. (ClinicalTrials.gov: NCT01534754).

Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals.

Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.

The Trop-2 signalling network in cancer growth.

Our findings show that upregulation of a wild-type Trop-2 has a key controlling role in human cancer growth, and that tumour development is quantitatively driven by Trop-2 expression levels. However, little is known about the regulation of expression of the TROP2 gene. Hence, we investigated the TROP2 transcription control network. TROP2 expression was shown to depend on a highly interconnected web of transcription factors: TP63/TP53L, ERG, GRHL1/Get-1 (grainyhead-like epithelial transactivator), HNF1A/TCF-1 (T-cell factor), SPI1/PU.1, WT (Wilms' tumour)1, GLIS2, AIRE (autoimmune regulator), FOXM1 (forkhead box M1) and FOXP3, with HNF4A as the major network hub. TROP2 upregulation was shown to subsequently drive the expression and activation of CREB1 (cyclic AMP-responsive-element binding protein), Jun, NF-κB, Rb, STAT1 and STAT3 through induction of the cyclin D1 and ERK (extracellular signal regulated kinase)/MEK (MAPK/ERK kinase) pathways. Growth-stimulatory signalling through NF-κB, cyclin D1 and ERK was shown to require an intact Trop-2 cytoplasmic tail. Network hubs and interacting partners are co-expressed with Trop-2 in primary human tumours, supporting a role of this signalling network in cancer growth.

Upregulation of Trop-2 quantitatively stimulates human cancer growth.

Trop-2 is a calcium signal transducer that is associated with transformed cell growth in experimental systems. However, its role in human cancer remains essentially unknown. In this study, we profiled Trop-2 expression in normal human tissues at the mRNA and protein levels. We then systematically compared Trop-2 mRNA and protein levels in tumours with their tissues of origin. We find that Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Thus, we investigated the outcome of Trop-2 upregulation on tumour growth. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. On the other hand, we found no evidence of tumour-associated TROP2 mutations, nor of TROP2 induction of oncogenic transformation per se. Our data support a model where above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.

An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling.

The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance, which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand that abrogates receptor-mediated signaling. Toward this end, we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. Assessment of human tumor cell lines, as well as early passage tumor cells revealed that MP-RM-1 effectively inhibited both NRG-1ß-dependent and -independent ErbB-3 activation. The antagonizing effect of MP-RM-1 was of non-competitive type, as binding of [(125)I]-labeled NRG-1ß to ErbB-3 was not influenced by the antibody. MP-RM-1 treatment led, in most instances, to decreased ErbB-3 expression. In addition, MP-RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in two human tumor xenograft nude mouse models. Treatment with the antibody was associated with a decreased ErbB-3 and Akt phosphorylation and ErbB-3 expression in the excised tumor tissue. Collectively, these results indicate that MP-RM-1 has the potential to interfere with signaling by ErbB-3 and reinforce the notion that ErbB-3 could be a key target in cancer-drug design.

An immunohistochemically positive E-cadherin status is not always predictive for a good prognosis in human breast cancer.

BACKGROUND: in primary breast cancers dichotomic classification of E-cadherin expression, according to an arbitrary cutoff, may be inadequate and lead to loss of prognostic significance or contrasting prognostic indications. We aimed to assess the prognostic value of high and low E-cadherin levels in a consecutive case series (204 cases) of unilateral node-negative non-lobular breast cancer patients with a 8-year median follow-up and that did not receive any adjuvant therapy after surgery. METHODS: expression of E-cadherin was investigated by immunohistochemistry and assessed according to conventional score (0, 1+, 2+, 3+). Multiple correspondence analysis was used to visualise associations of both categorical and continuous variables. The impact of E-cadherin expression on patients outcome was evaluated in terms of event-free survival curves by the Kaplan-Meier method and proportional hazard Cox model. RESULTS: respect to intermediate E-cadherin expression values (2+), high (3+) or low (0 to 1+) E-cadherin expression levels had a negative prognostic impact. In fact, both patients with a low-to-nil (score 0 to 1+) expression level of E-cadherin and patients with a high E-cadherin expression level (score 3+) demonstrated an increased risk of failure (respectively, hazard ratio (HR)=1.71, confidence interval (CI)=0.72-4.06 and HR=4.22, CI=1.406-12.66) and an interesting association with young age. CONCLUSIONS: the findings support the evidence that high expression values of E-cadherin are not predictive for a good prognosis and may help to explain conflicting evidence on the prognostic impact of E-cadherin in breast cancer when assessed on dichotomic basis.

Steroids as part of combination treatment: the future for the management of macular edema?

Diabetic macular edema (DME), defined as a retinal thickening involving or approaching the center of the macula, plays a major role in vision loss related to diabetic retinopathy. This article presents an in-depth analysis of therapeutic perspectives on DME by means of an approach based on combination therapy with steroids. Corticosteroid drugs have been demonstrated to both inhibit the expression of vascular endothelial growth factor (VEGF) and the VEGF gene, and to have antiinflammatory properties. A treatment algorithm is provided regarding the management of DME. While grid laser photocoagulation remains the first-line therapy for focal vasogenic DME, diffuse DME can be effectively treated by means of intravitreal injections of corticosteroids. Recalcitrant DME can also be managed beneficially with intravitreal steroids. The management of DME is complex, and often multiple treatment approaches are needed. Each form of DME should be properly classified and specifically treated. The combination treatment has still an important role in the combined treatment options for DME.

Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction.

The overall effect of brain zinc (Zn(2+)) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn(2+) can exacerbate the pathological features of AD, a deficit of Zn(2+) intake has also been shown to increase the volume of amyloid plaques in AD transgenic mice. In this study, we investigated the effect of dietary Zn(2+) supplementation (30 p.p.m.) in a transgenic mouse model of AD, the 3xTg-AD, that expresses both ß amyloid (Aß)- and tau-dependent pathology. We found that Zn(2+) supplementation greatly delays hippocampal-dependent memory deficits and strongly reduces both Aß and tau pathology in the hippocampus. We also evaluated signs of mitochondrial dysfunction and found that Zn(2+) supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn(2+) supplementation greatly increases the levels of brain-derived neurotrophic factor (BDNF) of treated 3xTg-AD mice. In summary, our data support the idea that controlling the brain Zn(2+) homeostasis may be beneficial in the treatment of AD.

Macular hole and intravitreal injection of triamcinolone acetonide for macular edema due to central retinal vein occlusion.

PURPOSE: To report a case of macular hole progression after intravitreal injection of triamcinolone acetonide (IVTA) for chronic macular edema secondary to nonischemic central retinal vein occlusion (CRVO). METHODS: A 33-year-old woman with massive macular edema after CRVO underwent IVTA. Optical coherence tomography (OCT) and fluorescein angiography were performed before and after the procedure. RESULTS: At the 1-week IVTA injection control, the patient's best-corrected visual acuity improved from 20/400 to 20/200 and OCT detected a progression of macular hole stage. CONCLUSIONS: IVTA steroid injection may provide a significant improvement in macular edema, but injection-related complications may occur such as this uncommon macular reaction resulting in permanent visual loss.

Perception of, and anxiety levels induced by, laser treatment in patients with sight-threatening diabetic retinopathy. A multicentre study.

AIMS: To investigate how laser treatment is perceived, in terms of anxiety and awareness, by diabetic patients attending four centres in Northern Italy with specific interest and expertise in diabetic retinopathy, where work settings and flow are organized differently. METHODS: The Hospital Anxiety and Depression Scale (HADS), Family Apgar-List of Threatening Experiences (FA-LTE), State-Trait Anxiety Inventories 1 and 2 (STAI-1 and STAI-2) questionnaires were completed by 259 patients, 131 waiting for laser treatment and 128 control subejcts awaiting non-intervention visits. Open questions were also asked on whether patients had ever heard the word 'laser' and whether they could describe laser treatment. RESULTS: High scores were detected by HADS, STAI-1 and STAI-2 among patients waiting for photocoagulation. Anxiety was greater in women and people with poor schooling. After controlling for centres, gender, previous laser treatment and schooling, HADS and STAI-1 remained significantly lower among persons waiting for non-intervention visits. Having received photocoagulation previously did not modify anxiety. Anxiety was lower in those centres where facilities and resources were more patient-oriented. Most patients could neither describe photocoagulation nor explain why they were about to receive it, but had a negative perception and some described it with words evoking cruelty and pain. CONCLUSIONS: These data suggest that laser treatment is experienced as an event that causes anxiety. Preoperative education and counselling may help to reduce fear and patients' avoidance of treatment.

Macular thickness measured by optical coherence tomography (OCT) in diabetic patients.

PURPOSE: 1) To compare macular thickness (MT) by optical coherence tomography (OCT) in diabetics and controls; 2) to assess the relationship between MT and stage of diabetic retinopathy (DR) and macular edema (ME); 3) to quantify MT changes after laser treatment for ME. METHODS: One-hundred and thirty-seven patients with diabetes mellitus (216 eyes) were admitted to the study and examined by stereo-color fundus photos, retinal fluorangiography and OCT. DR was classified as: 1) no DR (46 eyes: 21.3%); 2) background DR (66 eyes: 30.6%); 3) pre-proliferative DR (50 eyes: 23.1%); 4) proliferative DR (54 eyes: 25%). The study group was then divided into three ME groups: 1) no edema (65 eyes: 30.1%); 2) not clinically significant ME (no CSME) (45 eyes: 20.8%); 3) clinically significant macular edema (CSME) (106 eyes: 49.1%). Three-month follow-up tomograms were taken to evaluate eyes laser-treated only for ME. The control group consisted of 50 eyes of 50 non-diabetic, age- and sex-matched subjects. RESULTS: MT was 369.3 +/- 163.2 microm in diabetics and 161.9 +/- 12.9 microm in controls (p < 0.001). In the four DR groups it was: 1) 211.0 +/- 37.6 microm; 2) 370.8 +/- 159.6 microm; 3) 419.1 +/- 138.2 microm; 4) 456.1 +/- 162.0 microm (p<0.001). In the three ME groups, MT was: 1)227.8 +/- 53.4 microm; 2) 321.8 +/- 124.2 microm; 3) 476.2 +/-146.6 microm (p < 0.001). In the 52 eyes treated with laser photocoagulation of the posterior pole only and with a follow-up > 3 months, MT before and after treatment was 468.2 +/- 83. 17 microm and 372.1 +/- 120.63 microm. CONCLUSIONS: MT was greater in diabetics than controls and tended to increase with DR and ME severity. OCT is a sensitive technique for detecting early diabetic macular abnormalities and quantifying their reduction after laser treatment.

Florid diabetic retinopathy (FDR): a long-term follow-up study.

PURPOSE: To evaluate efficacy of laser photocoagulation and pars-plana vitrectomy in patients with FDR. METHODS: Eighty-eight patients (155 eyes) with FDR were retrospectively evaluated (mean age 27 +/- 6.0 years; proportion of females 66%; insulin-dependent diabetes 100%; mean duration of diabetes 16.5 +/- 5.8 years; poor metabolic control 83%). The eyes were divided in two groups: group I: 136 eyes amenable to laser photocoagulation and, when necessary, to vitrectomy afterwards (45/136); group II: 19 eyes subjected directly to vitrectomy. RESULTS: In group I (mean follow-up 54.2 +/- 38.7 months) the initial visual acuity (IVA) was 0.61 +/- 0.30 and the final visual acuity (FVA) was 0.47 +/- 0.34; in the 45 vitrectomized eyes IVA was 0.15 +/- 0.24 and FVA was 0.19 +/- 0.25. FDR regressed in 75% and worsened in 25% of the cases. In group II (mean follow-up 46.4 +/- 36.3 months) IVA was 0.1 +/- 0.14 and FVA 0.14 +/- 0.22. FDR regressed in 32% and worsened in 68% of cases. CONCLUSIONS: FDR remains a cause of severe visual impairment in diabetics. Patients at risk of FDR are young females with long-standing, poorly controlled insulin-dependent diabetes. Panretinal laser photocoagulation prior to vitrectomy is beneficial; information on this severe form of retinopathy is essential to ensure prompt diagnosis and improve its unfavorable clinical course.

[Diagnosis of severity as a basic parameter in the treatment of acute biliary pancreatitis]. / La diagnosi di gravità come parametro fondamentale per il trattamento della pancreatite acuta biliare.

BACKGROUND: Acute biliary pancreatitis (ABP) still retains high morbidity (15-50%) and mortality (20-35%). Therefore it appears to be crucial to clearly assess the aetiological factors (50% of idiopathic are in fact biliary pancreatitis) and to establish their severity in order to plan the appropriate treatment. METHODS: 58 ABP patients were diagnosed by ultrasound (77.5%) or by laboratory findings (22.4%). Following Ranson and APACHE II scoring 17 cases (29.3%) were classified as severe, 41 (70.6%) as mild. All patients with severe ABP, had emergency ERCP + ES (within 24-48 hrs) followed by LC (< or = 10 days). Patients with mild ABP had LC within 10 days; in these cases IOC was always done. RESULTS: In severe cases operative endoscopy cured pancreatic inflammation in 12 cases. Subsequent LC never showed serious morbidity, apart from subcutaneous emphysema in one case. In 5 cases laparotomy was required since pancreatic necrosis was present, with 60% mortality. In patients with mild pancreatitis LC was successfully performed in all cases, with 7.3% morbidity. IOC showed choledochal stones in 31.7% of cases, while in severe cases stones in the biliary tree were shown in 88.2% of cases. CONCLUSIONS: In conclusion ABP treatment is always surgical, and almost always with minimally-invasive procedures in severe cases (ERCP + ES with LC < or = 10 days) if surgery is performed within 24-48 hrs as well as in mild cases (LC + IOC) when surgery is done within 10 days.

Axial length in patients with diabetes.

PURPOSE: To investigate the relationship between axial length and retinal involvement in patients with diabetes. METHODS: A total of 157 consecutive patients with diabetes underwent biometry. The patients were divided into three groups, according to retinopathy: 44 without retinopathy, 37 with background retinopathy, and 76 with proliferative retinopathy. To compare axial length in diabetic versus nondiabetic subjects, a control group of 157 healthy subjects with age and sex distribution similar to the diabetic group was selected from an orthopedic clinic. We investigated in the diabetic group whether the axial length was related to specific type of diabetes (non-insulin-dependent or insulin-dependent), duration of disease, presence of retinopathy, or laser treatment. To eliminate the confounding effect of myopia, we excluded all patients with axial length greater than 24 mm from the two groups. Comparison of diabetic patients without retinopathy versus nondiabetic subjects was also performed. RESULTS: Diabetic patients presented shorter axial lengths compared with the controls (mean +/- standard deviation, 22.4+/-1.3 mm versus 23.4+/-1.3 mm; P<0.001). Significantly shorter axial lengths were found in the background and proliferative retinopathy groups compared with the group without retinopathy (22.0+/-1.2 mm and 22.1+/-1.1 mm versus 23.2+/-1.4 mm, respectively; P<0.05). No difference in axial length was found between the diabetic patients without retinopathy and the nondiabetic subjects (P = 0.3). Multivariate analyses showed that retinopathy was negatively correlated with axial length (P<0.01). Including only the patients with axial length under 24 mm, we obtained similar results. CONCLUSION: Axial length is shorter in diabetic patients than in nondiabetic subjects. Within the diabetic group, patients with retinopathy had shorter axial lengths than did patients without retinopathy.