Detecting gene signature activation in breast cancer in an absolute, single-patient manner.

BACKGROUND: The ability to reliably identify the state (activated, repressed, or latent) of any molecular process in the tumor of a patient from an individual whole-genome gene expression profile obtained from microarray or RNA sequencing (RNA-seq) promises important clinical utility. Unfortunately, all previous bioinformatics tools are only applicable in large and diverse panels of patients, or are limited to a single specific pathway/process (e.g. proliferation). METHODS: Using a panel of 4510 whole-genome gene expression profiles from 10 different studies we built and selected models predicting the activation status of a compendium of 1733 different biological processes. Using a second independent validation dataset of 742 patients we validated the final list of 1773 models to be included in a de novo tool entitled absolute inference of patient signatures (AIPS). We also evaluated the prognostic significance of the 1773 individual models to predict outcome in all and in specific breast cancer subtypes. RESULTS: We described the development of the de novo tool entitled AIPS that can identify the activation status of a panel of 1733 different biological processes from an individual breast cancer microarray or RNA-seq profile without recourse to a broad cohort of patients. We demonstrated that AIPS is stable compared to previous tools, as the inferred pathway state is not affected by the composition of a dataset. We also showed that pathway states inferred by AIPS are in agreement with previous tools but use far fewer genes. We determined that several AIPS-defined pathways are prognostic across and within molecularly and clinically define subtypes (two-sided log-rank test false discovery rate (FDR) <5%). Interestingly, 74.5% (1291/1733) of the models are able to distinguish patients with luminal A cancer from those with luminal B cancer (Fisher's exact test FDR <5%). CONCLUSION: AIPS represents the first tool that would allow an individual breast cancer patient to obtain a thorough knowledge of the molecular processes active in their tumor from only one individual gene expression (N-of-1) profile.

Incidence and outcome of pulmonary embolism following popliteal venous repair in trauma cases.

OBJECTIVES AND DESIGN: Popliteal vein repair and ligation are the two main approaches to the treatment of the venous component of major, complex, knee injuries with vascular involvement. We have studied the incidence of pulmonary embolism following popliteal vein repair in trauma cases using computed tomography (CT) angiography and report the outcome. MATERIAL AND METHODS: From June 2006 to December 2009, 45 patients with popliteal vein injury were operated on in our vascular unit using lateral venorrhaphy, end-to-end anastomosis, a saphenous vein interposition graft and venous patch repair. All the patients were operated on using a medial approach to the knee. On the third postoperative day, all patients underwent a colour Doppler scan of the repaired popliteal vein to study patency, and pulmonary artery CT angiography using a 64-slice multidetector CT scan unit to establish the incidence of pulmonary embolism. RESULTS: The number of patients treated by each method were: lateral venorrhaphy 20 (44%), end-to-end anastomosis 13 (29%), saphenous vein interposition graft 9 (20%) and venous patch repair three (7%). Two patients (4%) died because of sudden cardio-respiratory arrest the day after surgery with massive bilateral pulmonary artery embolism at autopsy. Popliteal colour duplex ultrasound imaging showed seven (16%) cases of complete vein thrombosis and seven (16%) cases of partial vein thrombosis. CT angiography showed pulmonary embolism in 11 (26%) patients. From seven patients with complete thrombosis three patients, and from seven patients with incomplete thrombosis five patients showed pulmonary embolism on CT angiography. Other than two cases of early mortality, five (12%) patients developed clinical manifestations of pulmonary embolism and 11 (26%) patients had pulmonary embolism detected by CT angiography. Seven (16%) of our patients had mild-to-severe pulmonary embolism and 13 patients (29%) had proven pulmonary embolism. The total mortality rate was 7%. CONCLUSION: A surprisingly high incidence of pulmonary embolism was observed after popliteal vein repair in civil trauma patients. Additional prophylactic methods such as using higher doses of heparin and using inferior vena cava (IVC) filters might be needed to prevent this potentially fatal complication.

Photobiomodulation therapy improves the growth factor and cytokine secretory profile in human type 2 diabetic fibroblasts.

Impaired wound healing is a common complication of diabetes mellitus (DM) and the underlying mechanism of this impairment is still unclear. Fibroblast, as the main reconstructing cell, secretes some critical growth factors and cytokine contributing to wound healing. It is well known that DM alters the behavior of these cells and photobiomodulation therapy (PBMT) compensates some impairments in diabetic fibroblasts. Therefore, the aim of the present study was to demonstrate the impact of diabetes and the role of PBMT through low level laser irradiation on secretory profile of human diabetic fibroblasts. Primary human dermal fibroblasts from normal (HDFs) and diabetic (DHDFs) donors were harvested. For PBMT, the DHDFs were irradiated with a Helium-Neon laser at 632.8 nm wavelength and energy density of 0.5 J/cm2, as laser treated group (LT-DHDFs). Next, some cellular behaviors and secretory profiling array for 60 growth factors/cytokines were investigated in LT-DHDFs and then compared with those of controls. The data showed that the PBMT could compensate such impairments occurred in DHDFs in terms of viability, proliferation, and migration. Furthermore, considering our novel findings, out of those 20 growth factors/cytokines involved in cell proliferation, immune system regulation, and cell-cell communication pathways, which significantly decreased in DHDF as compared with HDFs, the PBMT could compensate seven in LT-DHDFs as compared with DHDFs. The seven growth factor/cytokines, which are mainly involved in cell-cell communication, positive regulation of cell proliferation, and chemokine mediated pathway included BDNF, Eotaxin-3, FGF6, FGF7, Fractalkine, fit-3ligand, and GCP-2. Therefore, it is suggested that scrutinizing these differentially secreted molecules and the impaired pathways in DHDFs, in combination with those compensated in LT-DHDFs, could raise our knowledge to manage diabetic ulcer through a feasible and cost effective intervention, specifically PBMT.

Comparing vein with collagen impregnated woven polyester prosthesis in above-knee femoropopliteal bypass grafting.

OBJECTIVE: Despite many clinical studies, there is still uncertainty as to whether venous material is superior to prosthetic materials for femoropopliteal reconstruction proximal to the knee joint. A prospectively randomized clinical trial was designed to evaluate the effectiveness of reversed saphenous vein in comparison with that of collagen impregnated woven polyester prosthesis in above-knee arterial reconstruction. METHODS: In a 3-year period, 103 above-knee femoropopliteal bypass graft operations were performed and followed in 85 patients (52 male, 33 female). The indication for operation was severe claudication in 74 cases, rest pain in 7 cases, and ulceration in 4 cases. For the bypass graft, a reversed saphenous vein was used in each of 51 cases, and a collagen impregnated woven polyester prosthesis was used in each of 52 cases. Preoperative risk factors were diabetes (24%), a history of myocardial infarction (23%), and current status with respect to smoking (74%). There was no hospital mortality; 5% of patients had minor postoperative complications. RESULTS: After 2 years of follow-up, the primary patency was 81% for saphenous vein and 67% for collagen impregnated woven polyester prosthesis (P=0.065); the secondary patency was 81% for saphenous vein and 77% for collagen impregnated woven polyester prosthesis (P=0.298). During this follow-up period of 2 years, we found no statistically significant difference in primary and secondary patency between saphenous vein and collagen impregnated woven polyester prosthesis. We found no predictive factor for the occlusion of either bypass graft. CONCLUSION: The use of collagen impregnated woven polyester prosthesis above the knee is a reasonable alternative in femoropopliteal bypass grafting that is associated with acceptable short-term patency rates.

Use of vein graft as a tendon sheath substitute following tendon repair: an innovative technique in tendon surgery.

OBJECTIVES: This is a new technique for managing tendon repair that may improve the results of existing methods. METHODS: In a prospective randomized clinical trial, 210 patients were divided into two groups of test and control. All patients had flexor tendon injuries, involving zone 2. They were new or old tendon injuries or complications of previous repairs. In the test group (105 patients), a modified Kessler repairing of tendons with 3-0 prolene was used, followed by a core suture of running 6-0 nylon or prolene epitendinous suture. After the tendon repair, a segment of vein through which the tendon had been passed before or a patch of vein, as a tendon sheath substitute, was used to repair the sheath defects. The results in a span of six months of follow-up were compared with those of the control group whereon 105 patients were operated under the conventional technique--the modified Kessler method. RESULTS: We assessed the results by measuring the range of motion of the MCP joint in the follow-up period and we graded them as excellent, good, fair and poor. In the test group we had 86% excellent, 11% good, 3% fair and 0% poor results, and in the control group, 0% excellent, 12% good, 38% fair and 50% poor results. The differences were significant (p<0.005). CONCLUSIONS: Our preliminary results appeared encouraging when compared with the outcomes achieved by the conventional tendon repair technique. As this technique reduces the adhesion formation, improves tendon nourishment, and decreases the need of intensive physiotherapy, it may substitute the conventional one and become a standard technique in the future.