Short duration of upper extremity lymphedema correlates with a favorable cytokine response after lymph node transfer surgery

Vascularized lymph node transfer surgery (VLNT) can provide benefit to lymphedema patients. Cytokines mayplaya role in the development oflymphedema and in the regeneration oflymphatic vessels after VLNT. Ourprimary aim was to investigate whether the VLNTpatients have a specific cytokine profile. Our secondary aim was to see whether the preoperative lymphedema or severity affects the postoperative cytokine response. Wound exudate was gathered from 18 patients undergoing VLNT on the first and sixth postoperative day (POD). The concentrations of IL-10, TNF-alpha, TGF-beta 1 and VEGF-C were analyzed using enzyme-inked immune-sorbent assays. A general score was generated to assess the benefit ofthe surgery. The changes in cytokine concentrations (1(st) POD-6th POD) were correlated with the pre- andpostoperative lymphedema related factors. A shorter duration oflymphedema preoperatively correlated with an increase in the concentration of IL-10 and TNF-beta during the first six PODs (IL-10: r=0.495, p=0.051; TNF-alpha: p=0.006) and a decrease in the concentration of 7VF-111 (r= p=0.020). The increase ofthe concentration of TNF-alpha during the first six PODs also correlated with a greater total general score (r=0.775, p=0.005) and hence indicated a better response to the surgery. The patients with a shorter duration oflymphedema preoperatively had a more favorable cytokine response during the first six PODs after VLNT

Low TGF-β1 in Wound Exudate Predicts Surgical Site Infection After Axillary Lymph Node Dissection

PurposeSurgical site infection (SSI) after axillary lymph node dissection (ALND) for breast cancer increases morbidity and delays the onset of adjuvant treatment. Only a few studies have investigated the feasibility of wound exudate analysis in SSI prediction. This study assessed changes in cytokine levels in postsurgical wound exudate after ALND and examined their predictive value for the early diagnosis of SSI.MethodsAn observational prospective pilot study was conducted in 47 patients with breast cancer undergoing ALND. Wound exudate samples were collected on the first and sixth postoperative days (POD). Interleukin (IL)-1α, IL-1β, IL-4, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), transforming growth factor beta1 (TGF-β1) and vascular endothelial growth factor (VEGF) C and D levels were measured by immunoassay. Patients were followed to detect SSI.ResultsSSI was diagnosed in 8/47 (17.0%) patients. Four SSI patients were hospitalized and treated with intravenous antibiotics. The concentration of TGF-β1 in wound exudate was significantly lower on POD#1 in the SSI group compared to the no SSI group (p=0.008). The receiving operator characteristics (ROC) curve for TGF-β1 showed an area under curve of 0.773 (p=0.0149) indicating good diagnostic potential. On POD#6, the concentration of TGF-β1 remained significantly lower (p=0.043) and the concentrations of IL-10 (p=0.000) and IL-1β (0.004) significantly higher in the SSI group compared to the no SSI group.ConclusionTo our knowledge, this is the first study suggesting a predictive role of wound exudate TGF-β1 levels for SSI. Our results suggest that the risk for SSI can be detected already on POD#1 and that the assessment of TGF-β1 levels in the wound exudate after ALND can provide a usefull method for the early detection of SSI. The key findings of this pilot study warrant verification in a larger patient population.</p

Preperitoneal Fat Grafting Inhibits the Formation of Intra-abdominal Adhesions in Mice

BACKGROUND: Adhesion formation contributes to postoperative complications in abdominal and gynaecological surgery. Thus far, the prevention and treatment strategies have focused on mechanical barriers in solid and liquid form, but these methods are not in routine use. As autologous fat grafting has become popular in treatment of hypertrophic scars because of its immunomodulatory effects, we postulated that fat grafting could also prevent peritoneal adhesion through similar mechanisms.METHODS: This was a control versus intervention study to evaluate the effect of fat grafting in the prevention on peritoneal adhesion formation. An experimental mouse model for moderate and extensive peritoneal adhesions was used (n = 4-6 mice/group). Adhesions were induced mechanically, and a free epididymal fat graft from wild type or CAG-DsRed mice was injected preperitoneally immediately after adhesion induction. PET/CT imaging and scaling of the adhesions were performed, and samples were taken for further analysis at 7 and 30 days postoperation. Macrophage phenotyping was further performed from peritoneal lavage samples, and the expression of inflammatory cytokines and mesothelial layer recovery were analysed from peritoneal tissue samples.RESULTS: Fat grafting significantly inhibited the formation of adhesions. PET/CT results did not show prolonged inflammation in any of the groups. While the expression of anti-inflammatory and anti-fibrotic IL-10 was significantly increased in the peritoneum of the fat graft-treated group at 7 days, tissue-resident and repairing M2 macrophages could no longer be detected in the fat graft at this time point. The percentage of the continuous, healed peritoneum as shown by Keratin 8 staining was greater in the fat graft-treated group after 7 days.CONCLUSIONS: Fat grafting can inhibit the formation of peritoneal adhesions in mice. Our results suggest that fat grafting promotes the peritoneal healing process in a paracrine manner thereby enabling rapid regeneration of the peritoneal mesothelial cell layer.</div

Vapaan rasvasiirteen vaikutukset vatsaontelon kiinnikkeiden hoidossa

Vatsaontelon sisäisen leikkauksen jälkeen muodostuvat vatsansisäiset kiinnikkeet ovat merkittävä kliininen ongelma. Kiinnikkeitä muodostuu etenkin avotekniikalla tehtyjen leikkausten yhteydessä. Kiinnikkeiden muodostuminen aiheuttaa kroonista vatsan ja lantion alueen kipua, hedelmättömyyttä sekä suolitukoksia ja johtaa usein uusintaleikkauksiin. Suomessa saatavilla olevien kiinnikkeiden muodostumista estävien tuotteiden vaikutusmekanismit perustuvat vaurioituneiden vatsakalvopintojen mekaaniseen eristämiseen. Kyseisten tuotteiden kliininen näyttö ja käyttö on vähäistä. Vatsaontelon kiinnikkeiden muodostuminen muistuttaa ihon haavan paranemista monin tavoin. Vapaita rasvasiirteitä käytetään fibroottisten tilojen kuten hypertrofisten ja kiristävien arpien hoidossa. Tämän tutkimuksen tarkoituksena oli selvittää vapaan rasvasiirteen vaikutusmekanismia vatsaontelon sisäisten kiinnikkeiden ehkäisyssä hiirimallin avulla. Tutkimuksessa käytettiin kokeellista hiirimallia, jossa hiirille tehtiin vatsaontelon sisäinen avoleikkaus ja kiinnikkeet indusoitiin mekaanisesti vaurioittamalla caecumin ja peritoneumin pintaa skalpellilla. Samassa yhteydessä koeryhmälle injisoitiin vaurioalueen preperitoneaalitilaan vapaa rasvasiirre. Hiirille tehtiin 30 vuorokauden kohdalla 18F-FDG PET/TT-kuvaus ja hiiret lopetettiin. Virtaussytometristen määritysten osalta käytössä oli 7 vuorokauden aikapiste, jossa hiiret lopetettiin. Lopettamisen jälkeen kiinnikkeiden aste arvioitiin ja kiinnikkeet valokuvattiin. Peritoneumista ja rasvasiirteestä kerättiin näytteet histologisia, immunohistokemiallisia, virtaussytometrisia ja qRT-PCR-analyyseja varten. Rasvasiirre vähensi merkittävästi kiinnikkeiden muodostumista. Rasvasiirreryhmällä kiinnikkeet olivat kalvomaisen ohuita ja helposti irroteltavissa. Kiinnikekontrolliryhmässä kiinnikkeet olivat pääsääntöisesti tiukkoja, yhtenäisiä ja niiden irrotteluun tarvittiin leikkaus. Anti-inflammatorisen ja anti-fibroottisen sytokiinin, IL-10, ilmentyminen oli merkittävää rasvasiirreryhmässä 7 vuorokauden kuluttua toimenpiteestä. Kudosmakrofagit ja anti-inflammatoriset M2-tyypin makrofagit olivat kadonneet siirretystä rasvasta 7 vuorokauden kohdalla ja rasvasiirteestä peräisin olevaa solukkoa ei ollut tunnistettavissa peritoneumista kerätyistä näytteistä. Peritoneumin parantumisen osalta määritettiin keratiini-8-värjäyksen osuus, joka oli suurempi rasvasiirreryhmässä 7 vuorokauden kohdalla. Rasvasiirre ehkäisee kiinnikkeiden muodostumista hiirillä. Tulostemme pohjalta tämä saattaa johtua siitä, että rasvasiirre edistää vaurioituneen vatsakalvopinnan paranemista, ilman kiinnikkeen muodostumista. Kehittämämme uusi lähestymistapa vatsaontelon kiinnikkeiden ehkäisyyn on autologinen ja edullinen, lisäksi kliininen sovellettavuus on edullista, koska rasvasiirrekirurgiaa hyödynnetään jo plastiikkakirurgian alalla

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele