Fabio Santanelli di Pompeo

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Proposal for a Monitoring Protocol.

Background: The authors report four cases of breast implant–associated anaplastic large cell lymphoma (ALCL) from a single institution and propose a multidisciplinary protocol. Methods: From 2012 to 2014, four breast implant–associated ALCL cases were diagnosed. The authors performed the original operation, and no patients were referred to their practice. Cases 1, 2, and 4 were CD4+/CD30+/ALK− ALCL with previous textured-implant reconstruction, whereas case 3 was CD8+/CD30+/ALK− ALCL with previous polyurethane-implant augmentation. A retrospective study of all patients who underwent breast implant positioning was performed to identify any misdiagnosed cases. Results: Of 483 patients, 226 underwent reconstruction with latissimus dorsi flap and prosthesis, 115 had skin-sparing/nipple-sparing mastectomy and prosthesis, 117 underwent an expander/implant procedure, and 25 underwent breast augmentation. Fifty-eight cases (12 percent) underwent implant replacement for capsular contracture, 15 (3.1 percent) experienced late-onset seroma, and four (0.83 percent) had both capsular contracture and seroma. Seventy-seven symptomatic patients (16 percent) underwent surgical revision (capsulectomy/capsulotomy) and/or seroma evacuation. The second look on histologic specimens did not identify misdiagnosed cases. A multidisciplinary protocol for suspected implant-associated ALCL was established. Ultrasound and cytologic examinations are performed in case of periprosthetic effusion. If implant-associated ALCL is diagnosed, implant removal with capsulectomy is performed. If disseminated disease is detected through positron emission tomography/computed tomography of the total body, the patient is referred to the oncology department. Conclusions: A multidisciplinary protocol is mandatory for both early diagnosis and patient management. Until definitive data emerge regarding the exact etiopathogenesis of breast implant–associated ALCL, the authors suggest offering only autologous reconstruction if patients desire it. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Targeted next generation sequencing of breast implant-associated anaplastic large cell lymphoma reveals mutations in JAK/STAT signalling pathway genes, TP53 and DNMT3A

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is an uncommon neoplasm occurring in women with either cosmetic or reconstructive breast implants (Clemens et al, 2016). Until now, most studies have focused on defining the clinico-pathological features of BI-ALCL, leading to its inclusion as a new provisional entity, a subtype of anaplastic lymphoma kinase (ALK)-negative ALCL, in the revised World Health Organization classification of lymphoid malignancies (Swerdlow et al, 2016). BI-ALCL is characterized by the presence of CD30 large atypical lymphocytes frequently confined to the peri-implant seroma fluid. Nevertheless, solid infiltrating masses and cases pursuing an aggressive clinical course have been reported. The surgical and pathological staging system designed by Clemens et al (2016) suggests that BI-ALCL has a pattern of progression similar to that of solid tumours rather than non-Hodgkin lymphomas, and that the effusionand solid-types might represent different stages of the same disease rather than two distinct variants. The molecular pathogenesis and mechanisms of progression of BI-ALCL, however, remain largely unknown, thus limiting the identification of biomarkers that enable disease prognostication and optimal treatment. Hence, we performed targeted next generation sequencing of seven BI-ALCL, identified in the archives of three institutions over 7 years, to investigate the presence of underlying somatic mutations. Informed consent was obtained from patients and the study was performed in accordance with the Declaration of Helsinki. DNA extracted from micro-dissected tumour cells of formalin-fixed paraffin-embedded BI-ALCL samples (QIAamp DNA Mini kit; Qiagen, Germantown, MD, USA) was used to prepare DNA libraries (Sureselect kit; Agilent Technologies, Santa Clara, CA, USA). Sequencing was performed on a HiSeq2500 (Illumina, San Diego, CA, USA) using a panel of 465 cancerassociated genes (Table SI). The sequence data were aligned to the human reference genome (hg19) and variants were identified using NextGENe (SoftGenetics, State College, PA, USA). The average read depth of the samples was 4009 (Table SII). Somatic mutations were identified by comparison of variants detected in lymphoma with those from matched constitutional DNA. Common variants (>1% frequency) present in the 1000 genomes database, and the database of Columbia University were removed. Somatic mutations were classified using the prior literature, and two different prediction algorithms (SIFT http://sift.bii.a-star.edu.sg and Polyphen-2 [PP2] http://genetics.bwh.harvard.edu/pph2/). The exonic somatic variants were confirmed by bidirectional Sanger sequencing using Big-Dye terminators v3.1 (Applied Biosystems, Carlsbad, CA, USA). The clinical and pathological features of the patients are summarized in Table I. Informative results were obtained in five of seven cases (Table SII); analysis failed in two cases due to the poor quality of DNA. Five somatic variants affecting four genes were identified in two cases: one intronic and four within coding regions (Fig 1 and Table SIII). A STAT3 missense variant (p.S614R) affecting the SH2 domain, which mediates STAT3 dimerization, was detected in one of these two BI-ALCLs. JAK/STAT signalling is implicated in cell proliferation, differentiation and apoptosis, and aberrant activation of STAT3 has been reported in several human cancers associated with persistent immune stimulation and/or inflammation. Notably, the gain-of-function mutation (S614R) was recently described in one BI-ALCL (Blombery et al, 2016), and has been reported in angioimmunoblastic T cell lymphomas, chronic lymphoproliferative disorders of natural killer cells, and T-cell large granular lymphocyte leukaemias (Odejide et al, 2014). Moreover, gain-of-function mutations in STAT3 have been reported in 18% of systemic ALK-negative ALCLs and 5% of cutaneous ALCLs (Crescenzo et al, 2015). An in vitro study using BI-ALCL-derived cell lines also showed activation of the JAK/STAT pathway through autocrine production of interleukin 6, suggesting a possible pathogenic mechanism (Lechner et al, 2012). A frameshift deletion causing a premature stop codon in SOCS1 (p.P83Rfs*20) was detected in the BI-ALCL harbouring the STAT3 mutation. SOCS1 is a negative feedback regulator of the JAK/STAT pathway. The p.P83Rfs*20 mutation deletes the C-terminal SOCS box domain and partially deletes the SH2 domain, which downregulates the kinase activity of JAK. Loss-of-function mutations of SOCS1, leading to constitutive activation of JAK/STAT signalling, have been described in B-cell lymphomas and in classical Hodgkin lymphomas (Mottok et al, 2009). Moreover, SOCS1 was found to be silenced by miR-155 in ALK-negative ALCL (Merkel et al, 2015). Mutations in STAT3 and SOCS1 suggest that deregulated activation of the JAK/STAT pathway may contribute to the development of BI-ALCL. A missense mutation of TP53 (p.D259Y) affecting the DNA binding domain was also observed in the Correspondence

The axillary versus internal mammary recipient vessel sites for breast reconstruction with diep flaps: A retrospective study of 256 consecutive cases

The aim of this study is to present our experience on the use of various recipient sites for deep inferior epigastric perforator (DIEP) flap breast reconstruction and compare them by means of objective data. Two hundred fifty six DIEP flap breast reconstructions, performed between March 2004 and May 2011, were retrospectively analyzed. Only unilateral reconstructions were included in the study and divided into three groups depending on the recipient site choice: internal mammary vessels (IMV) (n = 52), thoracodorsal vessels (TDV) (n = 109), and circumflex scapular vessels (CSV) (n = 95). Clinical records of each patient were reviewed to acquire relevant data such as operative time, postoperative complications, and use of a second vein anastomosis. CSV group showed a statistically significant lower operative time (4.92 ± 0.54 hours) compared to TDV (5.67 ± 1.01 hours) and IMV groups (6.75 ± 1.09 hours) (P < 0.001). Second vein anastomosis was performed in 84 cases (88.1%) of CSV, in 85 cases (77.9%) of TDV, and in 18 cases (35.1%) of IMV groups (P < 0.001). No significant differences were observed among groups regarding risk factors and complications (P > 0.05). The axillary vessels seem to be the ideal recipient site because of reduced operative time and increased possibility to perform a second vein anastomosis. Among them, CSV can be safely used due to following advantages: easy dissection, larger vessel caliber, and optimal flap insetting. Moreover, their location does not expose them completely to radiotherapy consequences.

Gynecomastia: A systematic review.

Abstract Background: Gynecomastia is a common medical problem presenting in nearly a third of the male population. Treatment for gynecomastia can be either pharmacological or surgical. Patients with gynecomastia often experience affected quality-of-life. The aim of this systematic review was to analyze the quality of evidence of the current literature in relation to different treatment modalities and Quality-of-Life in patients with gynecomastia. Methods: A systematic search of the literature was performed in PubMed, Medline, Scopus, The Cochrane Library, and SveMed+ in accordance with the PRISMA statement. All searches were undertaken between September–November 2014. The PICOS (patients, intervention, comparator, outcomes, and study design) approach was used to specify inclusion criteria. Methodological quality was graded according to MINORS. Quality of evidence was rated according to GRADE. Data from the included studies were extracted based on study characteristics, participants specifics, type of intervention/treatment, and type of outcome measures into data extraction forms. Results: A total of 134 abstracts were identified in the literature search. Seventeen studies met inclusion criteria, 14 concerning treatment and three concerning Quality-of-Life. All studies were non-randomised with a high risk of bias and very low quality of evidence according to GRADE. Conclusions: Several different surgical methods have been described with good results, minimal scars, and various levels of complications. Traditional surgical excision of glandular tissue combined with liposuction provides most consistent results and a low rate of complications. Pubertal gynecomastia may safely be managed by pharmacological anti-oestrogen treatment.

Tips and tricks for DIEP flap breast reconstruction in patients with previous abdominal scar

The aim of this study was to analyze outcomes of patients who had prior abdominal operations and underwent DIEP flap breast reconstruction and to describe technical strategies to insure well‐vascularized flap‐harvest minimizing abdominal donor‐site complications. All patients who underwent DIEP flap breast reconstruction between 2004 and 2014 were reviewed and divided into a control group (CG) and a scar group (SG). Patient demographics, operative details, flap and donor‐site complications were analyzed and compared. For all of the scars, DIEP flap design was not modified, but a standardized approach was developed according to the type and location of the scar, available vascular pedicle, perforator locations, and the required flap tissue for breast reconstruction. Two hundred and eighty patients underwent 292 flaps in CG and 107 underwent 111 flaps in SG. Pfannenstiel, McBurney, laparoscopic, midline and subcostal were the most common previous incisions. There were no significant differences between groups regarding demographics, flap and mastectomy weight, active smoking, or radiation status (P > 0.05). No significant differences were observed in DIEP flap loss (P = 0.909), partial flap loss (P=0.799), or fat necrosis (P=0.871) and in the rate of abdominal donor‐site complications between groups (P > 0.05). SG had a significantly higher mean operative time than CG (P=0.034). Medial raw was a negative risk‐factor for flap complications, while BMI (>25.1 kg/m2) and smoking‐history were significant predictors for donor‐site complications. With careful preoperative planning and appropriate technical strategies, successfully DIEP flap breast reconstruction can be performed without increased flap and donor‐site complications in patients with preexisting abdominal scars.

One-stage DIEP flap breast reconstruction: Algorithm for immediate contralateral symmetrization

The aim of this study was to investigate clinical and aesthetic results of simultaneous contralateral balancing procedures in unilateral DIEP flap reconstructions by means of a symmetrization algorithm. Between 2004 and 2013, 335 patients underwent DIEP flap breast reconstruction with 48 patients (mean age 51.8 years, range 32–69 years) undergoing contralateral procedure. Patients were divided in Group‐A including 31 cases who underwent one‐stage procedure and Group‐B including 17 cases who underwent staged procedure. A symmetrization algorithm was proposed to plan immediate breast reduction/mastopexy. The groups were homogeneous regarding patients age, BMI, mastectomy and flap weight (P > 0.05). All flaps survived. No complications were observed to the mastectomy skin flaps and to the reduction mammaplasty/mastopexy procedures in both groups. The mean operation time was 5 h in Group‐A while 5 h and 37 min in Group‐B (P = 0.0682). Contralateral procedures included 23 breast reductions and 8 mastopexies in Group‐A, while 10 breast reductions and 7 mastopexies were performed in Group‐B. Two and 6 patients required revision of the balancing procedure in Group‐A and Group‐B, respectively. The follow‐up time was 47.3 months (range 14–120 months) in Group‐A and 91.3 months (range 41–110 months) in Group‐B. Volume, upper/lower pole shape, projection, breast mound placement, IMF, symmetry, overall appearance, and general satisfaction sub‐items obtained high‐score evaluation without significant difference between the two groups (P > 0.05). One‐stage DIEP flap reconstruction by means of the symmetrization algorithm resulted in comparable aesthetic outcomes and patient satisfaction to a staged procedure.

Gynecomastia in Patients with Prostate Cancer: A Systematic Review

Introduction Gynecomastia and/or mastodynia is a common medical problem in patients receiving antiandrogen (bicalutamide or flutamide) treatment for prostate cancer; up to 70% of these patients result to be affected; furthermore, this can jeopardise patients’ quality of life. Aims To systematically review the quality of evidence of the current literature regarding treatment options for bicalutamide-induced gynecomastia, including efficacy, safety and patients’ quality of life. Methods The PubMed, Medline, Scopus, The Cochrane Library and SveMed+ databases were systematically searched between January 1, 2000 and December 31, 2014. All searches were undertaken between January and February 2015. The search phrase used was:”gynecomastia AND treatment AND prostate cancer”. Two reviewers assessed 762 titles and abstracts identified. The search and review process was done in accordance with the PRISMA statement. The PICOS (patients, intervention, comparator, outcomes and study design) process was used to specify inclusion criteria. Quality of evidence was rated according to GRADE. Main Outcome Measures Primary outcomes were: treatment effects, number of complications and side effects. Secondary outcome was: Quality of Life. Results Eleven studies met the inclusion criteria and are analysed in this review. Five studies reported pharmacological intervention with tamoxifen and/or anastrozole, either as prophylactic or therapeutic treatment. Four studies reported radiotherapy as prophylactic and/or therapeutic treatment. Two studies compared pharmacological treatment to radiotherapy. Most of the studies were randomized with varying risk of bias. According to GRADE, quality of evidence was moderate to high. Conclusions Bicalutamide-induced gynecomastia and/or mastodynia can effectively be managed by oral tamoxifen (10–20 mg daily) or radiotherapy without relevant side effects. Prophylaxis or therapeutic treatment with tamoxifen results to be more effective than radiotherapy.

The use of the serratus anterior muscle vascular pedicle as recipient site in DIEP flap transfer for breast reconstruction

Currently, the choice for recipient vessels in microvascular breast reconstruction is made between axillary and internal mammary regions. The authors report their experience with anastomosis to a new, unconventional, axillary recipient vessel, the serratus anterior muscle vascular pedicle. Among 340 deep inferior epigastric perforator (DIEP) flap breast reconstructions performed between 2004 and 2013, 11 were successfully revascularised to the serratus anterior (SA) pedicle: In three cases, complications led to a salvage procedure, while in eight cases, anastomosis to this recipient site was electively planned. The pedicle was constantly present, with calibre always comparable to that of flaps pedicle. At the mean 24-month follow-up, no recipient site complications were observed. The SA muscle pedicle resulted as a reliable choice in salvage procedures and a suitable option for recipient vessel selection in elective cases.

Sensate anterolateral thigh perforator flap for ischiatic sores reconstruction in meningomyelocele patients.

Recidivating pressure sores are a frequent complication in meningomyelocele patients because of their limitation in motility and their scarce ability to monitor the pressure applied on insensate areas while seated. We report the utilization of the sensate pedicled anterolateral thigh perforator flap for reconstruction of ischiatic sores in meningomyelocele patients. Between May 2011 and September 2013, five patients underwent transfer of a sensate pedicled anterolateral thigh flap, by an intermuscular passageway through the upper thigh, to reach the ischial defect. Flap was properly harvested from the thigh after assessment of the lateral cutaneous femoral nerve sensitive area with the Pressure‐Specified Sensory Device. In all cases the flap reached the ischial defect harmlessly, healing was uneventful with no immediate nor late complications. Each patient showed persistence of sensitivity at the reconstructed area and no recurrent ischiatic sore was observed at mean follow‐up of 26.4 months. The sensate pedicled anterolateral thigh flap is a valuable solution for coverage of recurrent ischial sores in meningomyelocele patients, in which pressure consciousness is fundamental. The intermuscular passageway allows to reduce the distance between flaps vascular pedicle origin and the ischial defect, hence to use the more reliable skin from the middle third of the anterolateral thigh.

Diep flap sentinel skin paddle positioning algorithm

Although clinical examination alone or in combination with other techniques is the only ubiquitous method for flap monitoring, it becomes problematic with buried free‐tissue transfer. We present a DIEP flap sentinel skin paddle (SSP) positioning algorithm and its reliability is also investigated using a standardized monitoring protocol. All DIEP flaps were monitored with hand‐held Doppler examination and clinical observation beginning immediately after surgery in recovery room and continued postoperatively at the ward. Skin paddle (SP) position was preoperatively drawn following mastectomy type incisions; in skin‐sparing mastectomies types I–III a small SP (sSP) replaces nipple–areola complex; in skin‐sparing mastectomy type IV, SSP is positioned between wise‐pattern branches while in type V between medial/lateral branches. In case of nipple‐sparing mastectomy SSP is positioned at inframammary fold or in lateral/medial branches of omega/inverted omega incision if used. Three hundred forty‐seven DIEP flap breast reconstructions were reviewed and stratified according to SP type into group A including 216 flaps with large SP and group B including 131 flaps with SSP and sSP. Sixteen flaps (4.6%) were taken back for pedicle compromise, 13 of which were salvaged (81.25%), 11 among 13 from group A and 2 among 3 from group B. There was no statistical difference between the groups concerning microvascular complication rate (P = 0.108), and time until take‐back (P = 0.521) and flap salvage rate (P = 0.473) resulted independent of SP type. Our results suggest that early detection of perfusion impairment and successful flaps salvage could be achieved using SSP for buried DIEP flap monitoring, without adjunctive expensive monitoring tests.