Flap coverage for necrotising soft tissue infections: A systematic review.

BACKGROUND: Necrotising soft tissue infections (NSTI) are destructive and often life-threatening infections of the skin and soft tissue, necessitating prompt recognition and aggressive medical and surgical treatment. After debridement, the aim of surgical closure and reconstruction is to minimize disability and optimize appearance. Although skin grafting may fulfil this role, techniques higher on the reconstructive ladder, including local, regional and free flaps, are sometimes undertaken. This systematic review sought to determine the circumstances when this is true, which flaps were most commonly employed, and for which anatomical areas. METHODS: A systematic review of the literature was conducted utilising electronic databases (Medline, Embase, Cochrane Library). Full text studies of flaps used for the management of NSTI's (including Necrotising Fasciitis and Fournier Gangrene) were included. The web-based program 'Covidence' facilitated storage of references and data management. Data obtained in the search included reference details (journal, date and title), the study design, the purpose of the study, the study findings, number of patients with NSTI included, the anatomical areas of NSTI involved, the types of flaps used, and the complication rate. RESULTS: After screening 4555 references, 501 full text manuscripts were assessed for eligibility after duplicates and irrelevant studies were excluded. 230 full text manuscripts discussed the use of 888 flap closures in the context of NSTI in 733 patients; the majority of these were case series published in the last 20 years in a large variety of journals. Reconstruction of the perineum following Fournier's gangrene accounted for the majority of the reported flaps (58.6%). Free flaps were used infrequently (8%), whereas loco-regional muscle flaps (18%) and loco-regional fasciocutaneous flaps (71%) were employed more often. The reported rate of partial or complete flap loss was 3.3%. CONCLUSION: Complex skin and soft tissue defects from NSTIs, not amenable to skin grafting, can be more effectively and durably covered using a spectrum of flaps. This systematic review highlights the important contribution that the plastic surgeon makes as an integral member of multidisciplinary teams managing these patients.

Complications following completion lymphadenectomy versus therapeutic lymphadenectomy for melanoma - A systematic review of the literature.

PURPOSE: Completion lymph node dissection (CLND) following a positive sentinel lymph node biopsy (SLNB) has been reported to be less morbid than lymphadenectomy for palpable disease (therapeutic lymph node dissection; TLND). The reporting of morbidity data can be heterogeneous, and hence no 'average' surgical complication rates of these procedures has been reported. This review aims to determine complications rates to inform patients undergoing surgery for metastatic melanoma. METHODS: A systematic review of English-language literature from 2000 to 2017, reporting morbidity information about CLND and TLND for melanoma, was performed. The methodological quality of the included studies was performed using the methodological index for non-randomised studies (MINORS) instrument and Detsky score. Pooled proportions of post-operative complications were constructed using a random effects statistical model. RESULTS: After application of inclusion and exclusion criteria, 18 articles progressed to the final analysis. In relation to TLND (1627 patients), the overall incidence of surgical complications was 39.3% (95% CI 32.6-46.2); including wound infection/breakdown 25.4% (95% CI: 20.9-30.3); lymphoedema 20.9% (95% CI: 13.8-29.1); and seroma 20.4% (95% CI: 15.9-25.2). For CLND (1929 patients), the overall incidence of surgical complications was 37.2% (95% CI 27.6-47.4); including wound infection/breakdown 21.6% (95% CI: 13.8-30.6); lymphoedema 18% (95% CI: 12.5-24.2); and seroma 17.9% (95% CI: 10.3-27). The complication rate was marginally lower for CLND but not to statistical significance. DISCUSSION: This study provides information about the incidence of complications after CLND and TLND. It can be used to counsel patients about the procedures and it sets a benchmark against which surgeons can audit their practice.

The Effect of Waiting Times for Postoperative Radiotherapy on Outcomes for Women Receiving Partial Mastectomy for Breast Cancer: a Systematic Review and Meta-Analysis.

AIMS: To determine the effect of delay in postoperative radiotherapy on local recurrence and overall survival in women receiving partial mastectomy for breast cancer. MATERIALS AND METHODS: This was a systematic review and meta-analysis of published literature. Relevant reports were identified from MEDLINE, EMBASE and the Cochrane Register of Controlled Trials in all languages from 1975 to April 2015, in addition to the abstracts from the annual meetings of major radiotherapy conferences from 2000 to 2011. Reference lists were hand searched to find additional relevant reports and OvidSP's 'Find Citing' function was used to find studies citing papers identified in the primary search. Studies were included if they met the following criteria: (i) all patients received partial mastectomy and radiotherapy, (ii) a delay from surgery to radiotherapy was reported and (iii) one or more of local control/failure and/or survival were reported. Observational studies and randomised controlled trials were included. Studies including patients with in situ disease were excluded. Studies were classified as high quality if they adequately controlled for factors known to be associated with the outcomes of interest. Study quality was independently assessed by three authors. Initial disagreements about three studies were resolved by consensus. Only high-quality studies were included in the primary analysis. Delay was modelled as a continuous variable and the relative risk of local recurrence and the relative risk of death are reported per month of delay. The study results were combined using a fixed-effects model. RESULTS: Thirty-four relevant publications including 79 616 patients were identified in the systematic review. Ten high-quality publications reported on local recurrence (13 291 patients) and four high-quality studies reported on overall survival (2207 patients). The relative risk of local recurrence per month of delay was 1.08 (95% confidence interval 1.02-1.14). The relative risk of death per month of delay was 0.99 (95% confidence interval 0.94-1.05). CONCLUSIONS: Delays in post-lumpectomy radiotherapy are associated with a significant increase in the risk of local recurrence. We recommend that waiting times for radiotherapy should be kept as short as reasonably achievable.

A systematic review of the evidence for telemedicine in burn care: with a UK perspective.

A comprehensive systematic review of telemedicine in burn care was carried out. Studies published between 1993 and 2010 were included. The main outcome measures were the level of evidence, technical feasibility, clinical feasibility, clinical management and cost effectiveness. The search strategy yielded 24 studies, none of which were randomised. There were only five studies with a control group, and in three of these the patients act as their own controls. Four studies performed quantitative cost analysis, and five more provide qualitative cost analysis. All studies demonstrate technical and clinical feasibility. If the significant potentials of telemedicine to assist in the acute triage, management guidance and outpatient care are to be realised, then research needs to be undertaken to provide evidence for such investment.

Telemedicine for acute plastic surgical trauma and burns.

Visual images can enhance communication over a distance. In the UK, plastic surgery provides services over large distances by a 'hub and spoke' model. Telemedicine could help to increase the efficiency of service for plastic surgery patients. Telemedicine, along with the impending Electronic Patient Record system could combine to improve communication, patient triage, record keeping, audit and could lead to a better quality of clinical care. Another benefit could be significant cost savings. We report our experience of the introduction of telemedicine to a Regional Plastic Surgery Service. Our first study compared assessments from images and patient examinations, which gave us confidence in the use of images [Jones SM, Milroy C, Pickford MA. Telemedicine in acute plastic surgical trauma and burns. Ann R Coll Surg Engl 2004;86:239-42]. We proceeded to a 10-week evaluation of all 973 referrals to our unit. We found that the system was used for a wide variety of injuries and for 42% of the 452 patients where the system was available. Initial resistance was overcome by the ease of use of the system, with both receiving and referring clinicians reporting benefits. The third phase was a 12-week prospective cohort study of 996 patients comparing the referrals with and without the telemedicine system. The system was available for 389 patients, and used for 243 patients (63%). The groups were analysed by a chi squared test and confidence interval calculation. We demonstrated a significant difference in the initial management of patients, with 10% more being booked directly to our Day Surgery Unit. There was a decrease in number of occasions when we were unable to accept a patient due to a lack of capacity. We found no change in the patients being managed with telephone only advice. We found that telemedicine is a valuable method of providing useful preliminary information in the referral process for injured patients and often significantly modifies their treatment and/or management plan. This has implications for the use of Information Technology resources and potentially the delivery of healthcare in relation to the management of injured patients.

Stopping warfarin therapy is unnecessary for hand surgery.

Interruption of appropriate therapeutic warfarin therapy imposes a risk of morbidity and mortality on the patient. Strategies to reduce the risks of interruption impose relatively large costs in terms of prolonged hospital stay, medication and coagulation monitoring. We report a series of 47 consecutive surgical episodes on the hands of 39 patients without interruption of therapeutic warfarin anticoagulation and with an INR of between 1.3 and 2.9. There was no difficulty with intraoperative haemostasis. Two patients had minor bleeding-related complications with no long-term sequelae. The authors conclude that interruption to warfarin therapy is unnecessary if the INR is less than 3.0 and therefore inappropriate for therapeutically anticoagulated patients undergoing hand surgery.

A point mutation in CD45 may be associated with an increased risk of HIV-1 infection.

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Here we show that abnormal CD45 splicing caused by a C77G transversion in exon A of the gene encoding CD45 (PTPRC) is associated with increased susceptibility to HIV-1 infection.

The exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans.

The leukocyte common (CD45) Ag is essential for normal T lymphocyte function and alternative splicing at the N terminus of the gene is associated with changes in T cell maturation and differentiation. Recently, a statistically significant association was reported in a large series of human thymus samples between phenotypically abnormal CD45 splicing and the presence of the CC chemokine receptor 5 deletion 32 (CCR5del32) allele, which confers resistance to HIV infection in homozygotes. We show here that abnormal splicing in these thymus samples is associated with the presence of the only established cause of CD45 abnormal splicing, a C77G transversion in exon A. In addition we have examined 227 DNA samples from peripheral blood of healthy donors and find no association between the exon A (C77G) and CCR5del32 mutations. Among 135 PBMC samples, tested by flow cytometric analysis, all those exhibiting abnormal splicing of CD45 also showed the exon A C77G transversion. We conclude that the exon A (C77G) mutation is a common cause of abnormal CD45 splicing and that further disease association studies of this mutation are warranted.

A deletion in the gene encoding the CD45 antigen in a patient with SCID.

SCID is a heterogeneous group of hereditary diseases. Mutations in the common gamma-chain (gamma(c)) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.

CD7 expression distinguishes subsets of CD4(+) T cells with distinct functional properties and ability to support replication of HIV-1.

Enrichment of a subset of CD4(+)CD45R0(+)CD7(-) T cells has been observed in HIV-infected individuals. We have investigated the ability of CD7(+) and CD7(-) T cells to support replication of HIV and show that virus replicates preferentially in CD7(+) cells. Several possible mechanisms that may underlie such differences in susceptibility to HIV were studied. Our data demonstrate that mitogen stimulation induces poor expression of CD25 and IL-2 in CD7(-) compared with CD7(+) cells. We also show that uninfected CD7(-) cells are more resistant to mitogen-induced apoptosis than CD7(+) cells. Our data support the view that the CD7(-) subset is inherently resistant to HIV replication and that this is due in part to reduced CD25 expression and IL-2 production.

A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans.

The leukocyte common antigen (CD45) is alternatively spliced, generating various isoforms expressed on hemopoietic cells. The splicing pattern of CD45 in T cells is altered in some individuals who show abnormal expression of high molecular weight isoforms containing exon A. The variant splicing pattern was shown to be associated with heterozygosity for a silent point mutation within CD45 exon A. This C to G transition is located 77 nucleotides downstream of the splice acceptor junction of exon A (198 bp total length). Here we report that this mutation is the cause of abnormal splicing. To isolate the mutant gene, somatic cell hybrids of lymphocytes with a CD45 splicing defect and a mouse lymphoid line were produced and clones expressing different isoforms of CD45 were isolated. Expression of the high molecular weight isoform containing exon A was associated with the mutation within exon A. All hybrids expressing the low molecular weight isoforms lacking exon A contained the normal allele of CD45 only. In addition, minigenes including this mutation were constructed and transfected into various cell lines (COS-7, HeLa, CHO). Semi-quantitative reverse transcription polymerase chain reaction showed an increase of more than tenfold in splicing to CD45RA (concomitant with a decrease in splicing to CD45RO) when compared with the normal minigene. Taken together, these results demonstrate a causal relationship between the mutation in CD45 exon A and the variant splicing pattern observed. The involvement of trans-acting splicing factors that interact with this region of CD45 pre-mRNA is currently under investigation.

Fibroblasts prevent apoptosis of IL-2-deprived T cells without inducing proliferation: a selective effect on Bcl-XL expression.

The apoptosis of human cytokine-deprived activated T cells can be prevented by a soluble mediator secreted by fibroblasts, epithelial and endothelial cells, and this rescue occurs with fibroblasts from different species. Fractionation of W138 fibroblast-conditioned medium indicated that the survival-promoting agent(s) were > 30,000 MW. The continuous presence of the survival factor was required for prevention of apoptosis, which did not involve the induction of proliferation. Nevertheless, the co-cultured T cells remained in a primed state. The expression of the apoptosis-inducing proteins Bax and CD95 (Fas/Apo-1) was either unchanged or slightly increased in fibroblast-rescued T cells, suggesting that constraints on survival still existed after co-culture. A fundamental observation in the present study was that although Bcl-2 was reduced, the levels of Bcl-XL was maintained in cytokine-deprived T cells by fibroblast co-culture. This suggests that fibroblasts and/or other stromal cells may promote activated T-cell survival by a selective effect on Bcl-XL expression, which is consistent with histological examination of activated T cells within lymphoid tissue in vivo. The rescued T cell could be re-activated by CD3 antibody, but only in the presence of CD28 co-stimulation, which induced both Bcl-2 and Bcl-XL expression and also proliferation. Thus, survival signals from stromal cells in tissue microenvironments may enable activated T-cell persistence in a primed but quiescent state, and our data suggest that the regulation of Bcl-XL expression may be central in this process. The further characterization of this process is essential to clarify how signals from stromal cells can influence the resolution and/or chronicity of immune responses in different tissues in vivo.

Intraperitoneal mitoxantrone or floxuridine: effects on time-to-failure and survival in patients with minimal residual ovarian cancer after second-look laparotomy--a randomized phase II study by theSouthwest Oncology Group.

A randomized phase II study of intraperitoneal (ip) mitoxantrone or floxuridine (FUDR) was performed for the treatment of minimal residual epithelial ovarian cancer found at second-look laparotomy after initial platinum-based chemotherapy. Entry was to take place within 30 days of reassessment laparotomies, with documentation of peritoneal metastases either microscopic or gross with cytoreduction to less than or equal to 1 cm in largest diameter. Patients were stratified by the site of the largest disease present (microscopic to 0.5 cm maximum diameter versus greater than 0.5 to 1 cm maximum diameter), by time of registration (< 14 days versus up to 30), and by serum CA-125 (< or = 35 versus >35 units/ml) prior to randomization to either ip mitoxantrone 10 mg/m2 every 2 weeks X 9 or ip floxuridine (FUDR) 3 g (total dose)/ day X 3 days every 3 weeks X 6 cycles. Implantable ip systems and 1.5-2 liters of normal saline were used to deliver the drugs of 83 patients registered between December 1988 and January 1994; there were 6 pathology exclusions and 9 surgical exclusions, and 1 nonevaluable patient for a total of 39 evaluable on mitoxantrone and 28 on FUDR being evaluable. FUDR is the choice for further study because of a progression-free survival exceeding 15% at 1 year over mitoxantrone and a median overall survival of 38 months. It should be emphasized again that the goal of a randomized phase II selection design is to select a winner for phase III testing should there be a substantial difference between the treatments with respect to the primary endpoint. Comparative conclusions between the treatment arms should not be attempted due to the inherently much smaller sample sizes. This should reemphasize the limitations in a comparison of efficacy; however, the toxicologic differences still emerge quite clearly.

Gonadotropin releasing hormone (GnRH) agonist therapy for reduction of leiomyoma volume.

A patient with menorrhagia, dysmenorrhea, and an enlarged uterus was treated with a GnRH agonist for leiomyoma volume reduction. A laser-assisted myomectomy yielded five tumors that did not appear to be well demarcated and had a combined weight of only 30 g. Postoperative pathologic evaluation revealed leiomyosarcoma with 22 mitoses per 10 high-power fields. The 8-month delay in therapy was associated with Stage IV, grade 3 disease at diagnosis. In rare cases GnRH agonist therapy may palliate symptoms and delay definitive surgical therapy of leiomyosarcoma, resulting in more advanced disease at diagnosis.

Characterization of a novel subset of T cells from human spleen that lacks L-selectin.

Human L-selection (LAM-1, Leu-8, TQ1, DREG 56) is a member of the 'selection' family of adhesion molecules. Antibodies to L-selectin have been shown to block the binding of T cells to peripheral lymph node high endothelial venules (HEV). Most unstimulated peripheral blood T cells express high levels of L-selectin whilst it is only weakly expressed on the majority of T cells from secondary lymphoid organs. We show here (a) that T cells from tonsil and lymph node up-regulate L-selectin when released from their microenvironment, (b) that in contrast, spleen contains a stable L-selectin negative subset, (c) that this subset remains surface L-selection negative after stimulation even though the T cells can respond by proliferation, (d) that this subset expresses minimal levels of LAM-1 mRNA and (e) that mucosal lymphocyte antigen (MLA) positive and T-cell receptor (TcR) gamma delta positive T cells found within the L-selectin negative population are similar to subsets of T cells found amongst lamina propria (LP) and intraepithelial lymphocytes (IEL) of the gut.

Menometrorrhagia in an oral contraceptive user.

Endometrial carcinoma is the most frequent malignancy of the female reproductive tract, and irregular vaginal bleeding is the most common presenting symptom. Endometrial carcinoma is found most commonly among postmenopausal women and is associated with obesity, nulliparity, and anovulation. Oral contraceptive (OC) use and tobacco smoking have been reported to protect against endometrial carcinoma. Irregular vaginal bleeding is a common side effect of OC therapy. We report the case of an obese, premenopausal nulliparous woman with normal menses who developed menometrorrhagia and was then found to have endometrial carcinoma despite her youth and her use of both tobacco and combination OC.

PIP: Endometrial carcinoma is the most frequent malignancy of the female reproductive tract, and irregular vaginal bleeding is its most common symptom. It is most common among postmenopausal women and is associated with obesity, nulliparity, and anovulation. Oral contraceptive (OC) use and tobacco smoking have been reported to protect against it. A 30-year-old nulligravida nulliparous woman presented with menometrorrhagia. She had had normal menses since age 11, she had smoked a pack of cigarettes a day for 15 years, and had been obese since age 15 (weighing 302 pounds). At age 26, she started taking a combination OC containing .1 mg ethynodiol diacetate and 35 mcg ethynyl estradiol (EE). 4 years later she gradually developed menorrhagia which improved upon changing the OC to .3 mg norgestrel and 30 mcg EE. Subsequently she developed early cycle metrorrhagia and was placed on .5 mg norgestrel and 50 mcg EE. She continued having early and midcycle breakthrough bleeding with clots. Physical examination and test results including a PAP smear were normal. She was taken to the emergency department because of continued bleeding. The uterus sounded to 14 cm. Curettings were consistent with grade 1-2, well-differentiated adenocarcinoma of the endometrium. 3 weeks later, she had total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal biopsy for cytological examination. The pelvis and the abdomen were free of metastasis. Histological examination revealed a superficially invasive, well-differentiated adenocarcinoma consistent with stage IB, grade 1%. Ploidy analysis uncovered 12.5% tetraploid, with 0% aneuploid or hyperploid cells with 8.5% of the cells in S phase and 21% in the proliferative phase. Both estrogen and progesterone receptors were positive. The ploidy analysis and receptor status were consistent with the low-grade nature of the lesions. Postoperative radiation was not recommended, and the patient was well 6 months postoperatively.